Compounds for the treatment of inflammatory disorders

ABSTRACT

This invention relates to compounds of the Formula (I):  
                 
 
     or a pharmaceutically acceptable salt, solvate or isomer thereof, which can be useful for the treatment of diseases or conditions mediated by MMPs, TNF-α or combinations thereof.

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of priority from U.S.Provisional Patent Application Serial No. 60/342,332, filed Dec. 20,2001, incorporated herein by reference.

BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] This invention relates to hydroxamic or carboxylic acidfunctional compounds that can inhibit the production of tumor necrosisfactor alpha (TNF-α), pharmaceutical compositions comprising suchcompounds, and methods of treatment using such compounds.

[0004] 1. Description

[0005] Tumor necrosis factor alpha (TNF-α) has been shown to play apivotal role in immune and inflammatory responses. Inappropriate orover-expression of TNF-α is a hallmark of a number of diseases,including rheumatoid arthritis (RA), Crohn's disease and sepsis.Inhibition of TNF-α production has been shown to be beneficial in manypreclinical models of inflammatory disease, making inhibition of TNF-αproduction or signaling an appealing target for the development of novelanti-inflammatory drugs.

[0006] Tumor necrosis factor alpha is a cell-associated cytokine that isprocessed from a 26 kd precursor form to a 17 kd active form. See BlackR. A. “Tumor necrosis factor-alpha converting enzyme” Int J Biochem CellBiol. 2002 January;34(1):1-5 and Moss M L, White J M, Lambert M H,Andrews RC.“TACE and other ADAM proteases as targets for drug discovery”Drug Discov Today. Apr. 1, 2001;6(8):417-426, each of which isincorporated by reference herein.

[0007] TNF-α has been shown to be a primary mediator in humans andanimals of inflammation, fever and acute phase responses, similar tothose observed during acute infection and shock. Excess TNF-α has beenshown to be lethal. Blocking the effects of TNF-α with specificantibodies can be beneficial in a variety of conditions, includingautoimmune diseases such as rheumatoid arthritis (Feldman et al, Lancet,(1994) 344, 1105), non-insulin dependent diabetes mellitus (Lohmander L.S. et al., Arthritis Rheum. 36 (1993) 1214-22) and Crohn's disease(Macdonald T. et al., Clin. Exp. Immunol. 81 (1990) 301).

[0008] Metalloproteinases (MP) are important in the uncontrolledbreakdown of connective tissue, including proteoglycan and collagen,leading to resorption of the extracellular matrix. This is a feature ofmany pathological conditions, such as rheumatoid and osteo-arthritis,corneal, epidermal or gastric ulceration; tumor metastasis or invasion;periodontal disease and bone disease. Normally these catabolic enzymesare tightly regulated at the level of their synthesis as well as attheir level of extracellular activity through the action of specificinhibitors, such as alpha-2-macroglobulins and TIMP (tissue inhibitor ofmetalloproteinase), which form inactive complexes with the MP's.

[0009] Osteo- and rheumatoid arthritis (OA and RA, respectively) aredestructive diseases of articular cartilage characterized by localizederosion of the cartilage surface. Findings have shown that articularcartilage from the femoral heads of patients with OA, for example, had areduced incorporation of radiolabeled sulfate over controls, suggestingthat there must be an enhanced rate of cartilage degradation in OA(Mankin et al. J. Bone Joint Surg. 52A (1970) 424-434). There are fourclasses of protein degradative enzymes in mammalian cells: serine,cysteine, aspartic and metalloproteinases. The available evidencesupports that it is the metalloproteinases that are responsible for thedegradation of the extracellular matrix of articullar cartilage in OAand RA. Increased activities of collagenases and stromelysin have beenfound in OA cartilage and the activity correlates with severity of thelesion (Mankin et al. Arthritis Rheum. 21, 1978, 761-766, Woessner etal. Arthritis Rheum. 26, 1983, 63-68 and Ibid. 27, 1984, 305-312). Inaddition, aggrecanase (a newly identified metalloproteinase enzymaticactivity) has been identified that provides the specific cleavageproduct of proteoglycan, found in RA and OA patients (Lohmander L. S. etal. Arthritis Rheum. 36, 1993, 1214-22).

[0010] Therefore, metalloproteinases (MP) have been implicated as thekey enzymes in the destruction of mammalian cartilage and bone. It canbe expected that the pathogenesis of such diseases can be modified in abeneficial manner by the administration of MP inhibitors, and manycompounds have been suggested for this purpose (see Wahl et al. Ann.Rep. Med. Chem. 25, 175-184, AP, San Diego, 1990).

[0011] Compounds that inhibit the production of TNF-α are therefore oftherapeutic importance for the treatment of inflammatory disorders.Recently it has been shown that a matrix metalloproteinase (MMP) orfamily of metalloproteinases, hereafter known as TNF-α convertases(TACE), as well as other MP's are capable of converting TNF-α from itsinactive to active form (Gearing et al Nature, 1994, 370, 555). Sinceexcessive TNF-α production has been noted in several disease conditionsalso characterized by MMP-mediated tissue degradation, compounds whichinhibit both MMPs and TNF-α production may also have a particularadvantage in diseases where both mechanisms are involved.

[0012] There are several patents which disclose hydroxamate andcarboxylate based MMP inhibitors.

[0013] W095/09841 describes compounds that are hydroxamic acidderivatives and are inhibitors of cytokine production.

[0014] European Patent Application Publication No. 574,758 A1, discloseshydroxamic acid derivatives as collagenase inhibitors. GB 2 268 934 Aand WO 94/24140 claim hydroxamate inhibitors of MMPs as inhibitors ofTNF-α production.

[0015] There is a need in the art for inhibitors of MMPS, in particularTNF-α convertase, which can be useful as anti-inflammatory compounds andcartilage protecting therapeutics. The inhibition of TNF-α convertaseand other metalloproteinases can prevent the degradation of cartilage bythese enzymes, thereby alleviating the pathological conditions of osteo-and rheumatoid arthritis.

SUMMARY OF THE INVENTION

[0016] In one embodiment, the present invention provides a compoundrepresented by Formula (I):

[0017] or a pharmaceutically acceptable salt, solvate or isomer thereof,wherein:

[0018] M is —(C(R³⁰)(R⁴⁰)_(m)—, wherein m is 1 to 6;

[0019] T is selected from the group consisting of R²¹-substituted alkyl,cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl,heteroaryl, —OR³, —C(O)R⁴, —C(O)OR³, —C(O)NR²⁴R²⁵, —C(O)NR²⁴OR³,—C(O)SR³, —NR²⁴R²⁵, —NR²⁵C(O)R⁴, —NR²⁵C(O)OR³, —NR²⁵C(O)NR²⁴R²⁵,—NR²⁵C(O)NR²⁴OR³, —SR³, —S(O)_(x)NR²⁴R²⁵, —S(O)_(x)NR²⁵OR³, —CN,—P(O)(R²⁴)(OR²⁴), —P(O)(OR²⁴)(OR²⁴), —C(R⁴)(═N(OR³)), —C(O)—AA—NR²⁴R²⁵and —C(O)—AA—NR²⁵OR³,

[0020] wherein each of the cycloalkyl, heterocycloalkyl, cycloalkenyl,heterocycloalkenyl, aryl and heteroaryl groups of T is independentlyunsubstituted or substituted with one to five independently selected R²⁰moieties which can be the same or different, each R²⁰ moiety beingindependently selected from the group of R²⁰ moieties below;

[0021] V is selected from the group consisting of alkyl, R²¹-substitutedalkyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl,aryl, heteroaryl, —OR³, —C(O)R⁴, —(CR²³R²⁴)_(n1)C(O)OR³, —C(O)NR²⁴R²⁵,—(CR²³R²⁴)_(n1)C(O)NR²⁵OR³, —C(O)SR³, —NR²⁴R²⁵, —NR²⁵C(O)R⁴,—NR²⁵C(O)OR³, —NR²⁵C(O)NR²⁴R²⁵, —NR²⁵C(O)NR²⁴OR³, —SR³,—S(O)_(x)NR²⁴R²⁵, —S(O)_(x)NR²⁵OR³, —CN, —P(O)(R²⁴)(OR²⁴),—P(O)(OR²⁴)(OR²⁴), —C(R⁴)(═N(OR³)), —C(O)—AA—NR²⁴R²⁵ and—C(O)—AA—NR²⁵OR,

[0022] wherein each of the cycloalkyl, heterocycloalkyl, cycloalkenyl,heterocycloalkenyl, aryl and heteroaryl groups of V is independentlyunsubstituted or substituted with one to three independently selectedR²⁰ moieties which can be the same or different, each R²⁰ moiety beingindependently selected from the group of R²⁰moieties below;

[0023] W is selected from the group consisting of

[0024]  a covalent bond, —(C(R³)(R⁴))_(n2)—, —O—, —S—, and —N(Z)—;

[0025] X is selected from the group consisting of alkylene,cycloalkylene, heterocycloalkylene, arylene, heteroarylene and —C≡C—,wherein each of the alkylene, cycloalkylene, heterocycloalkylene,arylene or heteroarylene groups of X is independently unsubstituted orsubstituted with one to four independently selected R²⁰ moieties whichcan be the same or different, each R²⁰ moiety being independentlyselected from the group of R²⁰moieties below;

[0026] U is selected from the group consisting of a covalent bond,—(C(R³)(R⁴))_(p)—, —Y—(C(R³)(R⁴))_(q)—, —(C(R³)(R⁴))_(t)—Y—, and —Y—;

[0027] Y is selected from the group consisting of —O—, —S(O)_(x)—,—N(Z)—, —C(O)—, —OC(O)—, —C(O)N(R²⁴)—, —N(R²⁴)C(O)N(R²⁵)—, —N(R²⁴)S(O)—,N(R²⁴)S(O)₂—, —S(O)N(R²⁴)—, and —S(O)₂N(R²⁴)—;

[0028] Z is selected from the group consisting of —R³, —C(O)R³,—S(O)_(x)R³ and —C(O)NR³R⁴;

[0029] n is 0 to 2;

[0030] n1 is 0 to 2;

[0031] n2 is 1 to 2;

[0032] p is 1 to 4;

[0033] q is 1 to 4;

[0034] t is 1 to 4;

[0035] v is 1 to 3;

[0036] x is 0 to 2;

[0037] y is 0 to 3;

[0038] AA is

[0039]  wherein R³¹ and R³² are the same or different and are eachindependently selected from the group consisting of H, alkyl,cycloalkyl, aryl, heteroaryl, —NR²⁴R²⁵, —(CH₂)₃NH(C═NH)NH₂, —CH₂C(O)NH₂,—CH₂C(O)OH, —CH₂SH, —CH₂S—SCH₂CH(NH₂)C(O)OH, —CH₂CH₂C(O)OH,—CH₂CH₂C(O)NH₂, —(CH₂)₄NH₂, —CH₂CH₂CH(OH)CH₂NH₂, —CH₂CH(CH₃)₂,—CH(CH₃)CH₂(CH₃), —CH₂CH₂SCH₃, —CH₂OH, —CH(OH)(CH₃),

[0040] or R³¹ and R³², together with the N to which R³¹ is attached andthe C to which R³¹ is attached, form a 5-membered ring which isunsubstituted or independently substituted with a hydroxyl group;

[0041] R¹ is selected from the group consisting of alkyl,R²¹-substituted alkyl, cycloalkyl, heterocycloalkyl, cycloalkenyl,heterocycloalkenyl, aryl, heteroaryl, —C≡CR³ and —CR³═CR⁴R⁵,

[0042] wherein each of the alkyl, cycloalkyl, heterocycloalkyl,cycloalkenyl, heterocycloalkenyl, aryl and heteroaryl groups of R¹ isindependently unsubstituted or substituted with one to fiveindependently selected R²⁰ moieties which can be the same or different,each R²⁰ moiety being independently selected from the group of R²⁰moieties below,

[0043] each R², R⁴ and R⁵ is the same or different and each isindependently selected from the group consisting of H, halo, alkyl,R²²-substituted alkyl, cycloalkyl, heterocycloalkyl, cycloalkenyl,heterocycloalkenyl, aryl, heteroaryl, —OR⁶, —C(O)R⁷, —C(O)OR⁶, —NR²⁴R²⁵,—NR²⁴C(O)R²⁵, —N(═C—O—NR²⁴R²⁵), —NR²⁴S(O)₂R²⁵,

[0044] wherein each of the cycloalkyl, heterocycloalkyl, cycloalkenyl,heterocycloalkenyl, aryl and heteroaryl groups of R², R⁴ and R⁵ isindependently unsubstituted or substituted with one to fourindependently selected alkyl, R²²-substituted alkyl or R²² moietieswhich can be the same or different, each R²² moiety being independentlyselected from the group of R²² moieties below;

[0045] each R³ is the same or different and is independently selectedfrom the group consisting of H, alkyl, R²²-substituted alkyl,cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl,heteroaryl, —OR⁶, —C(O)R⁷, —C(O)OR⁶, —NR²⁴R²⁵, —NR²⁴C(O)R²⁵,—N(═C—O—NR²⁴R²⁵) and —NR²⁴S(O)₂R²⁵,

[0046] each of the cycloalkyl, heterocycloalkyl, cycloalkenyl,heterocycloalkenyl, aryl and heteroaryl groups of R³ is independentlyunsubstituted or substituted with one to four independently selectedalkyl, R²²-substituted alkyl or R²² moieties which can be the same ordifferent, each R²² moiety being independently selected from the groupof R²² moieties below;

[0047] each R⁶ is independently selected from the group consisting of H,alkyl and —OCF₃;

[0048] each R⁷ is independently selected from the group consisting of H,alkyl, heteroaryl and —CF₃;

[0049] each R²⁰ is independently selected from the group consisting of:alkyl, R²¹-substituted alkyl, —OR³, halo, —CN, —NO₂, —NR²⁴R²⁵, —C(O)R³,—C(O)OR³, —C(O)NR²⁴R²⁵, —S(O)_(x)NR²⁴R²⁵, —S(O)_(x)R⁵, —CF₃, —OCF₃,—CF₂CF₃, —C(═NOH)R³, aryl, halo-substituted aryl, heteroaryl,cycloalkyl, heterocycloalkyl, —N(R²⁵)S(O)_(x)R⁵, —N(R²⁵)C(O)R⁵, and—N(R²⁵)C(O)NR²⁴R²⁵,

[0050] wherein each of the aryl, halo-substituted aryl, heteroaryl,cycloalkyl and heterocycloalkyl groups of R²⁰ is independentlyunsubstituted or substituted with one to four independently selected R²²moieties which can be the same or different, each R²² moiety beingindependently selected from the group of R²³ moieties below,

[0051] or two R²⁰ groups taken together with the carbon to which bothR²⁰ groups are attached is

[0052] R²¹ is one to three substituents independently selected from thegroup consisting of: —OR³, halo, —CN, —NO₂, —NR²⁴R²⁵, —C(O)R³, —C(O)OR³,—C(O)NR²⁴R²⁵, —S(O)_(x)NR²⁴R²⁵, —SO_(x)R⁵, —CF₃, —OCF₃, —CF₂CF₃,—C(═NOH)R³, R²³-substituted alkyl, aryl, heteroaryl, cycloalkyl,heterocycloalkyl, —N(R²⁵)S(O)_(x)R⁵, —N(R²⁵)C(O)R⁵, and—N(R²⁵)C(O)NR²⁴R²⁵;

[0053] wherein each of the aryl, halo-substituted aryl, heteroaryl,cycloalkyl, and heterocycloalkyl groups of R²¹ is independentlyunsubstituted or substituted with one to four independently selected R²³moieties which can be the same or different, each R²³ moiety beingindependently selected from the group of R²³ moieties below,

[0054] or two R²¹ groups taken together with the carbon to which bothR²¹ groups are attached is

[0055] each R²² is independently selected from the group consisting of:halo, alkynyl, aryl, heteroaryl, —OR²⁴, —(C₁-C₆ alkyl)-OR²⁴, —CN, —NO₂,—NR²⁴R²⁵, —C(O)R²³, —C(O)OR²³, —C(O)NR²⁴R²⁵, S(O)_(x)NR²⁴R²⁵,—S(O)_(x)R²³, —CF₃, —OCF₃, —CF₂CF₃, —C(═NOH)R²³, —N(R²⁴)S(O)_(x)R²⁵,—N(R²⁴)C(O)R²⁵, and —N(R²⁴)C(O)NR²⁴R²⁵,

[0056] or two R²² groups taken together with the carbon to which bothR²² groups are attached is

[0057] each R²³ is independently selected from the group consisting ofH, hydroxyl, halo and alkyl;

[0058] each R²⁴ is independently selected from the group consisting of Hand alkyl;

[0059] each R²⁵ is independently selected from the group consisting ofH, hydroxyl, alkyl, hydroxyalkyl, aryl, cycloalkyl, heteroaryl,—NR²⁴R²⁴, —(C₁ to C₆ alkyl)NR²⁴N²⁴, —CF₃ and —S(O)_(x)R²³;

[0060] each R²⁶ is independently selected from the group consisting ofH, hydroxyl, alkyl, hydroxyalkyl, aryl, cycloalkyl, heteroaryl and—NR³R⁴;

[0061] R²⁷ is independently selected from the group consisting ofheteroaryl, heterocycloalkyl and —NR²⁴R²⁵;

[0062] R³⁰ is independently selected from the group consisting of H andR²⁰ substituent groups above;

[0063] R⁴⁰ is independently selected from the group consisting of H andR²⁰ substituent groups above,

[0064] or R³⁰ and R⁴⁰, taken together with the carbon to which R³⁰ andR⁴⁰ are attached, is

[0065]  with the proviso that at least one of V or T is selected fromthe group consisting of —C(O)N(R³)(OR⁴), —C(O)OR³ and —C(O)NR²⁴R²⁵, and

[0066] when —(W)_(n)—X—U— is alkylene, R¹ is not alkyl.

[0067] In another embodiment, a compound of Formula I is provided withthe provisos that at least one of V or T is selected from the groupconsisting of

[0068] —C(O)N(R³)(OR⁴), —C(O)OR³ and —C(O)NR²⁴R²⁵, and

[0069] when —(W)_(n)—X—U— is alkylene, R¹ is not alkyl, and

[0070] when —(W)_(n)—X— is alkylene, —Y— is not —N(R²⁴)C(O)—, and

[0071] when one of T or V is —NR²⁵S(O)_(x)R³, the other of T or V is not—C(O)NR²⁵OR³.

[0072] Another aspect of the present invention is a compositioncomprising at least one of the above compounds. Methods of using thecompounds for the treatment of MMP and TNF-α mediated diseases andconditions also are provided. The compounds of the invention may be usedalone or in combination with other appropriate therapeutic agents.

[0073] Other than in the operating examples, or where otherwiseindicated, all numbers expressing quantities of ingredients, reactionconditions, and so forth used in the specification and claims are to beunderstood as being modified in all instances by the term “about.”

DETAILED DESCRIPTION OF THE INVENTION

[0074] In its several embodiments, the present invention provides anovel class of inhibitors of MMP and TNF-α convertase, pharmaceuticalcompositions containing one or more of the compounds, methods ofpreparing pharmaceutical formulations comprising one or more suchcompounds, and methods of treatment, prevention or amelioration of oneor more of the symptoms of inflammation.

[0075] In one embodiment, the present invention provides compounds whichare represented by structural Formula (I) above or a pharmaceuticallyacceptable salt, solvate or isomer thereof, wherein the various moietiesare as described above.

[0076] In one embodiment, m is 4. In another embodiment, m is 3. Inanother embodiment, m is 2. In another embodiment, m is 1.

[0077] In another embodiment, R³⁰ is H or —(C₁-C₆)alkyl. In anotherembodiment, R³⁰ is H.

[0078] In another embodiment, R⁴⁰ is H or —(C₁-C₆)alkyl. In anotherembodiment, R⁴⁰ is H.

[0079] In another embodiment, T is selected from the group consisting of—C(O)R⁴, —C(O)OR³,—C(O)NR²³R²⁵, and —C(O)NR²³OR³.

[0080] In one embodiment, T is —C(O)R⁴ in which R⁴ is a pyrrolidinylring that is unsubstituted or substituted with one to three R²² moietieswhich are each independently selected from the group consisting of—OR²⁴, —(C₁-C₆ alkyl)—OR²⁴ and —NR²³R²⁴. Preferred R²² moieties arehydroxyl, hydroxyalkyl and alkylamino and amino.

[0081] In another embodiment, T is —C(O)OR³ in which R³ is alkyl.

[0082] In another embodiment, T is —C(O)NR²³R²⁵ in which R²³ is H oralkyl and R²⁵ is H, alkyl or —(C₁ to C₆ alkyl)NR²³N²⁴.

[0083] In another embodiment, T is —C(O)NR²³OR³ in which R²³ is H oralkyl and R³ is H or alkyl.

[0084] In another embodiment, V is —C(O)NR²³OR³ in which R²³ is H oralkyl and R³ is H or alkyl. In another embodiment, V is —C(O)OR³ inwhich R³ is H or alkyl, such as methyl.

[0085] In another embodiment, W is —C(R³)(R⁴)— in which R³ is H and R⁴is H or W is a covalent bond.

[0086] In another embodiment, n is 1.

[0087] In another embodiment, X is arylene which is unsubstituted orsubstituted with one to two independently selected R²⁰ moieties whichcan be the same or different.

[0088] In another embodiment, X is phenylene which is unsubstituted orsubstituted with one or two halo substituents which can be the same ordifferent.

[0089] In another embodiment, X is a heteroarylene which isunsubstituted or substituted with one to two independently selected R²⁰moieties which can be the same or different.

[0090] In another embodiment, X is a heteroarylene selected from thegroup consisting of

[0091] which is unsubstituted or substituted with one or two halosubstituents, such as Cl, F or I, which can be the same or different.

[0092] In another embodiment, U is —Y—(C(R³)(R⁴))_(q)—. In anotherembodiment, Y is —O—. In another embodiment, q is 1, R³ is H or alkyland R⁴ is H or alkyl.

[0093] In another embodiment, R¹ is selected from the group consistingof cycloalkyl, aryl and heteroaryl, wherein each of the cycloalkyl, aryland heteroaryl groups of R¹ is independently unsubstituted orsubstituted with one to five independently selected R²⁰ moieties whichcan be the same or different, each R²⁰ moiety being independentlyselected from the group of R²⁰ moieties above.

[0094] In another embodiment, R¹ is a cycloalkyl group selected from thegroup consisting of cyclopropyl, cyclobutyl and cyclohexyl, wherein eachof the cycloalkyl groups is independently unsubstituted or substitutedwith one to five independently selected R²⁰ moieties which can be thesame or different, each R²⁰ moiety being independently selected from thegroup of R²⁰ moieties above, such as alkyl.

[0095] In another embodiment, R¹ is an aryl group selected from thegroup consisting of phenyl, naphthyl, indanyl andtetrahydronaphthalenyl, wherein each of the aryl groups is independentlyunsubstituted or substituted with one to five independently selected R²⁰moieties which can be the same or different, each R²⁰ moiety beingindependently selected from the group of R²⁰ moieties above, such asalkyl.

[0096] In another embodiment, R¹ is a heteroaryl group selected from thegroup consisting of chromanyl, quinolyl, isoquinolyl, triazolyl,pyridyl, imidazolyl, thiazolyl, benzodioxolyl and

[0097] wherein each of the heteroaryl groups is independentlyunsubstituted or substituted with one to five independently selected R²⁰moieties which can be the same or different, each R²⁰ moiety beingindependently selected from the group of R²⁰ moieties, such as alkyl,R²¹-substituted alkyl, halo, amino, carboxamide, aryl, heteroaryl,heterocycloalkyl and —OR³.

[0098] In another embodiment, R¹ is a fused bicyclic aryl group which isunsubstituted or substituted with one to three independently selectedR²⁰ moieties which can be the same or different.

[0099] In another embodiment, R¹ is a fused bicyclic heteroaryl groupwhich is unsubstituted or substituted with one to three independentlyselected R²⁰ moieties which can be the same or different.

[0100] In another embodiment, R² is H.

[0101] In another embodiment, each R³ is independently H, alkyl or aryl.

[0102] In another embodiment, each R⁴ is independently H, alkyl or aryl.

[0103] In another embodiment, each R⁵ is independently H, alkyl or aryl.

[0104] In another embodiment, each R²⁰ is independently selected fromthe group consisting of alkyl, R²¹-substituted alkyl, —OR³, halo, —CN,—NO₂, —NR³R⁴, —C(O)OR³, —S(O)_(x)R⁵, —CF₃, —OCF₃, aryl, heteroaryl,cycloalkyl, wherein each of the aryl, heteroaryl and cycloalkyl groupsof R²⁰ is independently unsubstituted or substituted with one to fourindependently selected R²² moieties which can be the same or different,each R²² moiety being independently selected from the group of R²³moieties.

[0105] In another embodiment, R²⁰ is a heteroaryl group selected fromthe group consisting of pyrazinyl, pyrrolyl, pyridyl and morpholinyl.

[0106] In another embodiment, R²⁰ is a cycloalkyl selected from thegroup consisting of cyclopropyl, cyclobutyl and cyclohexyl.

[0107] In another embodiment, R²⁰ is a heterocycloalkyl selected fromthe group consisting of piperazinyl and pyrrolidinyl.

[0108] In another embodiment, each R²⁰ moiety is selected from the groupconsisting of —(C₁-C₆)alkyl and aryl.

[0109] In another embodiment, M is —(C(R³⁰)(R⁴⁰)_(m)—, wherein m is 1 to4; V is —C(O)OR³ or —C(O)NR²⁵OR³; T is R²¹-substituted alkyl, —CN,—C(O)OR³, —C(O)NR²⁵OR³, —C(O)NR²⁴R²⁵, —C(O)R⁴ or —C(R⁴)(═N(OR³)); W is acovalent bond or —(C(R³)(R⁴))_(n2); X is arylene or heteroarylene, eachof which can be independently unsubstituted or substituted with one tofour independently selected R²⁰ moieties; R¹ is cycloalkyl, aryl,heteroaryl, each of which can be independently unsubstituted orsubstituted with one to four independently selected R²⁰ moieties; R² isH; and each of the other variables are as above in the Summary of theInvention.

[0110] A preferred group of compounds are shown in Table 1 below.

[0111] Except where stated otherwise, the following definitions applythroughout the present specification and claims. Additionally, alltechnical and scientific terms used herein have the same meaning as iscommonly understood by one skilled in the art to which this inventionbelongs. These definitions apply regardless of whether a term is used byitself or in combination with other terms. Hence the definition of“alkyl” applies to “alkyl” as well as to the “alkyl” portions of“alkoxy”, etc.

[0112] “Patient” or “subject” includes both humans and animals.

[0113] “Mammal” includes humans and other mammalian animals.

[0114] “Alkyl” means an aliphatic hydrocarbon group that may be straightor branched and comprising 1 to about 20 carbon atoms in the chain.Preferred alkyl groups contain 1 to about 12 carbon atoms in the chain.More preferred alkyl groups contain 1 to about 6 carbon atoms in thechain. Branched means that one or more lower alkyl groups such asmethyl, ethyl or propyl, are attached to a linear alkyl chain. “Loweralkyl” means a group having about 1 to about 6 carbon atoms in the chainwhich may be straight or branched. The alkyl may be substituted.

[0115] The phrase “R²¹-substituted alkyl” means that the alkyl group canbe substituted by one or more R²¹ substituents that may be the same ordifferent, each substituent being independently selected from the groupconsisting of R²¹ substituents listed above. Each of the aryl,halo-substituted aryl, heteroaryl, cycloalkyl and heterocycloalkylgroups of R²¹ can be unsubstituted or independently substituted with oneto four independently selected R²³ moieties which can be the same ordifferent, each R²³ moiety being independently selected from the groupof R²³ moieties above.

[0116] The phrase “R²²-substituted alkyl” means that the alkyl group canbe substituted by one or more R²² substituents that maybe the same ordifferent, each substituent being independently selected from the groupconsisting of R²² substituents listed above.

[0117] The phrase “R⁵²-substituted alkyl” means that the alkyl group canbe substituted by one or more R⁵² substituents which may be the same ordifferent, each substituent being independently selected from the groupconsisting of R²¹ substituents listed above.

[0118] “Alkenyl” means an aliphatic hydrocarbon group comprising atleast one carbon-carbon double bond and which may be straight orbranched and comprising 2 to about 15 carbon atoms in the chain.Preferred alkenyl groups have 2 to about 12 carbon atoms in the chain;and more preferably 2 to about 6 carbon atoms in the chain. Branchedmeans that one or more lower alkyl groups such as methyl, ethyl orpropyl, are attached to a linear alkenyl chain. “Lower alkenyl” means 2to about 6 carbon atoms in the chain which may be straight or branched.The alkenyl may be substituted and the term “R³⁵-substituted alkenyl”means that the alkenyl group may be substituted by one or moresubstituents which can be the same or different, each substituent beingindependently selected from the group consisting of R³⁵ substituentslisted above.

[0119] “Aryl” means an aromatic monocyclic or multicyclic (for example,bicyclic) ring system comprising about 5 to about 14 carbon atoms,preferably about 6 to about 10 carbon atoms. The aryl groups of T, V, X(arylene) and R¹ can be unsubstituted or independently substituted withone to five independently selected R²⁰ moieties which can be the same ordifferent, and are as defined herein. The aryl groups of R², R³, R⁴, R⁵and R²⁰ can be unsubstituted or independently substituted with one tofour independently selected R²² moieties which can be the same ordifferent, and are as defined herein. The aryl groups of R²¹ can beunsubstituted or independently substituted with one to fourindependently selected R²³ moieties which can be the same or different,and are as defined herein. Non-limiting examples of suitable aryl groupsinclude phenyl, naphthyl, indenyl, tetrahydronaphthyl and indanyl.

[0120] “Alkylene” refers to an alkanediyl group commonly having freevalencies on two carbon atoms. Non-limiting examples include methylene,propylene and the like.

[0121] “Arylene” is a bivalent group derived from an aromatichydrocarbon by removal of a hydrogen atom from two ring carbon atoms.Non-limiting examples include phenylene and the like.

[0122] “Heteroarylene” is a bivalent group derived from a heterocyclicaromatic compound by removal of a hydrogen atom from two ring atoms suchas, for example, the bivalent group derived from pyridine, pyrrole andthe like. The bonds to the parent moiety can be through different carbonring atoms, different hetero ring atoms or through a carbon ring atomand a hetero ring atom.

[0123] “Heteroaryl” represents cyclic aromatic groups of 5 or 6 atoms orbicyclic groups of 8 to 12 atoms having 1, 2 or 3 heteroatomsindependently selected from O, S or N, said heteroatom(s) interrupting acarbocyclic ring structure and having a sufficient number of delocalizedpi electrons to provide aromatic character, provided that the rings donot contain adjacent oxygen and/or sulfur atoms. Preferred monocyclicheteroaryls contain about 5 to about 6 ring atoms. Preferred bicyclicheteroaryls contain about 10 ring atoms. The heteroaryl groups of T, V,X (heteroarylene) and R¹ can be unsubstituted or independentlysubstituted with one to five independently selected R²⁰ moieties whichcan be the same or different, and are as defined herein. The heteroarylgroups of R², R³, R⁴, R⁵ and R²⁰ can be unsubstituted or independentlysubstituted with one to four independently selected R²² moieties whichcan be the same or different, and are as defined herein. The heteroarylgroups of R²¹ can be unsubstituted or independently substituted with oneto four independently selected R²³ moieties which can be the same ordifferent, and are as defined herein. The prefix aza, oxa or thia beforethe heteroaryl root name means that at least a nitrogen, oxygen orsulfur atom respectively, is present as a ring atom. Nitrogen atoms canform an N-oxide. All regioisomers are contemplated, e.g., 2-pyridyl,3-pyridyl and 4-pyridyl. Useful 6-membered heteroaryl groups includepyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, morpholinyl and the likeand the N-oxides thereof. Useful 5-membered heteroaryl rings includefuryl, triazolyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl,imidazolyl, pyrazolyl, isoxazolyl and the like. Typical bicyclic groupsare benzo-fused ring systems derived from the heteroaryl groups namedabove, e.g. quinolyl, isoquinolyl, phthalazinyl, quinazolinyl,benzofuranyl, benzothienyl, benzodioxolyl, indolyl and the like.

[0124] “Cycloalkyl” means a non-aromatic mono- or multicyclic ringsystem comprising about 3 to about 10 carbon atoms, preferably about 5to about 10 carbon atoms. Preferred cycloalkyl rings contain about 5 toabout 7 ring atoms. The cycloalkyl groups of T, V, X (cycloalkylene) andR¹ can be unsubstituted or independently substituted with one to fiveindependently selected R²⁰ moieties which can be the same or different,and are as defined herein. The cycloalkyl groups of R², R³, R⁴, R⁵ andR²⁰ can be unsubstituted or independently substituted with one to fourindependently selected R²² moieties which can be the same or different,and are as defined herein. The cycloalkyl groups of R²¹ can beunsubstituted or independently substituted with one to fourindependently selected R²³ moieties which can be the same or different,and are as defined herein. Non-limiting examples of suitable monocycliccycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl andthe like. Non-limiting examples of suitable multicyclic cycloalkylsinclude 1-decalinyl, norbornyl, adamantyl and the like.

[0125] “Halo” means fluoro, chloro, bromo, or iodo groups. Preferred arefluoro, chloro or bromo, and more preferred are fluoro and chloro.

[0126] “Cycloalkenyl” means a non-aromatic mono or multicyclic ringsystem comprising about 3 to about 10 carbon atoms, preferably about 5to about 10 carbon atoms which contains at least one carbon-carbondouble bond. Preferred cycloalkenyl rings contain about 5 to about 7ring atoms. The cycloalkenyl groups of T, V and R¹ can be unsubstitutedor independently substituted with one to five independently selected R²⁰moieties which can be the same or different, and are as defined herein.The cycloalkenyl groups of R², R³, R⁴, R⁵ and R²⁰ can be unsubstitutedor independently substituted with one to four independently selected R²²moieties which can be the same or different, and are as defined herein.The cycloalkenyl groups of R²¹ can be unsubstituted or independentlysubstituted with one to four independently selected R²³ moieties whichcan be the same or different, and are as defined herein. Non-limitingexamples of suitable monocyclic cycloalkenyls include cyclopentenyl,cyclohexenyl, cycloheptenyl, and the like. Non-limiting example of asuitable multicyclic cycloalkenyl is norbornyl.

[0127] “Heterocycloalkenyl” means a non-aromatic monocyclic ormulticyclic ring system comprising about 3 to about 10 ring atoms,preferably about 5 to about 10 ring atoms, in which one or more of theatoms in the ring system is an element other than carbon, for examplenitrogen, oxygen or sulfur atom, alone or in combination, and whichcontains at least one carbon-carbon double bond or carbon-nitrogendouble bond. There are no adjacent oxygen and/or sulfur atoms present inthe ring system. Preferred heterocycloalkenyl rings contain about 5 toabout 6 ring atoms. The prefix aza, oxa or thia before theheterocyclenyl root name means that at least a nitrogen, oxygen orsulfur atom respectively is present as a ring atom. Theheterocycloalkenyl groups of T, V and R¹ can be unsubstituted orindependently substituted with one to five independently selected R²⁰moieties which can be the same or different, and are as defined herein.The heterocycloalkenyl groups of R², R³, R⁴, R⁵ and R²⁰ can beunsubstituted or independently substituted with one to fourindependently selected R²² moieties which can be the same or different,and are as defined herein. The heterocycloalkenyl groups of R²¹ can beunsubstituted or independently substituted with one to fourindependently selected R²³ moieties which can be the same or different,and are as defined herein. The nitrogen or sulfur atom of theheterocycloalkenyl can be optionally oxidized to the correspondingN-oxide, S-oxide or S,S-dioxide. Non-limiting examples of suitablemonocyclic aza heterocycloalkenyl groups include1,2,3,4-tetrahydropyridyl, 1,2-dihydropyridyl,1,4,5,6-tetrahydropyrimidinyl, 2-pyrrolinyl, 2-imidazolinyl,2-pyrazolinyl, and the like. Non-limiting examples of suitable oxaheterocycloalkenyl groups include 3,4-dihydro-2H-pyranyl,dihydrofuranyl, and the like. Non-limiting example of a suitablemulticyclic oxa heterocycloalkenyl group is 7-oxabicyclo[2,2,1]heptenyl.Non-limiting examples of suitable monocyclic thia heterocycloalkenylrings include dihydrothiophenyl, dihydrothiopyranyl, and the like.

[0128] “Heterocycloalkyl” means a non-aromatic saturated monocyclic ormulticyclic ring system comprising about 3 to about 10 ring atoms,preferably about 5 to about 10 ring atoms, in which one or more of theatoms in the ring system is an element other than carbon, for examplenitrogen, oxygen or sulfur, alone or in combination. There are noadjacent oxygen and/or sulfur atoms present in the ring system.Preferred heterocycloalkyls contain about 5 to about 6 ring atoms. Theprefix aza, oxa or thia before the heterocyclyl root name means that atleast a nitrogen, oxygen or sulfur atom respectively is present as aring atom. The heterocycloalkyl groups of T, V, X (cycloalkylene) and R¹can be unsubstituted or independently substituted with one to fiveindependently selected R²⁰ moieties which can be the same or different,and are as defined herein. The heterocycloalkyl groups of R², R³, R⁴, R⁵and R²⁰ can be unsubstituted or independently substituted with one tofour independently selected R²² moieties which can be the same ordifferent, and are as defined herein. The heterocycloalkyl groups of R²¹can be unsubstituted or independently substituted with one to fourindependently selected R²³ moieties which can be the same or different,and are as defined herein. The nitrogen or sulfur atom of theheterocycloalkyl can be optionally oxidized to the correspondingN-oxide, S-oxide or S,S-dioxide. Non-limiting examples of suitablemonocyclic heterocycloalkyl rings include piperidyl, pyrrolidinyl,piperazinyl, morpholinyl, 1,3-dioxolanyl, tetrahydrofuranyl,tetrahydrothiophenyl and the like.

[0129] “Heterocycloalkylene” is a bivalent group derived from aheterocyclic cycloalkyl compound by removal of a hydrogen atom from tworing atoms such as, for example, the bivalent group derived frompiperazine and the like. The bonds to the parent moiety can be throughdifferent carbon ring atoms, different hetero ring atoms or through acarbon ring atom and a hetero ring atom.

[0130] “Hydroxyalkyl” means a HO-alkyl-group in which alkyl group is aspreviously defined. Preferred hydroxyalkyls contain lower alkyl.Non-limiting examples of suitable hydroxyalkyl groups includehydroxymethyl and 2-hydroxyethyl.

[0131] The term “optionally substituted” means optional substitutionwith the specified groups, radicals or moieties.

[0132] As a general note, any open-ended nitrogen atom with unfulfilledvalence in the chemical structures in this application refers to NH, orin the case of a terminal nitrogen, —NH₂. Similarly, any open-endedoxygen atom with unfulfilled valence in the chemical structures in thisapplication refers to —OH and any open-ended carbon atom with unfilledvalence is appropriately filled with —H.

[0133] As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

[0134] Prodrugs and solvates of the compounds of the invention are alsocontemplated herein. The term “prodrug”, as employed herein, denotes acompound that is a drug precursor which, upon administration to asubject, undergoes chemical conversion by metabolic or chemicalprocesses to yield a compound of formula I or a salt and/or solvatethereof. A discussion of prodrugs is provided in T. Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems (1987) Volume 14 of theA.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design,(1987) Edward B. Roche, ed., American Pharmaceutical Association andPergamon Press, both of which are incorporated herein by referencethereto.

[0135] “Solvate” means a physical association of a compound of thisinvention with one or more solvent molecules. This physical associationinvolves varying degrees of ionic and covalent bonding, includinghydrogen bonding. In certain instances the solvate will be capable ofisolation, for example when one or more solvent molecules areincorporated in the crystal lattice of the crystalline solid. “Solvate”encompasses both solution-phase and isolatable solvates. Non-limitingexamples of suitable solvates include ethanolates, methanolates, and thelike. “Hydrate” is a solvate wherein the solvent molecule is H₂O.

[0136] “Effective amount” or “therapeutically effective amount” is meantto describe an amount of compound of the present invention effective ininhibiting TNF-α or MMP and thus producing the desired therapeutic,ameliorative, inhibitory or preventative effect.

[0137] The compounds of formula I can form salts which are also withinthe scope of this invention. Reference to a compound of formula I hereinis understood to include reference to salts thereof, unless otherwiseindicated. The term “salt(s)”, as employed herein, denotes acidic saltsformed with inorganic and/or organic acids, as well as basic saltsformed with inorganic and/or organic bases. In addition, when a compoundof formula I contains both a basic moiety, such as, but not limited to apyridine or imidazole, and an acidic moiety, such as, but not limited toa carboxylic acid, zwitterions (“inner salts”) may be formed and areincluded within the term “salt(s)” as used herein. Pharmaceuticallyacceptable (i.e., non-toxic, physiologically acceptable) salts arepreferred, although other salts are also useful. Salts of the compoundsof the formula I may be formed, for example, by reacting a compound offormula I with an amount of acid or base, such as an equivalent amount,in a medium such as one in which the salt precipitates or in an aqueousmedium followed by lyophilization.

[0138] Exemplary acid addition salts include acetates, adipates,alginates, ascorbates, aspartates, benzoates, benzenesulforiates,bisulfates, borates, butyrates, citrates, camphorates,camphorsulfonates, cyclopentanepropionates, digluconates,dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates,glycerophosphates, hemisulfates, heptanoates, hexanoates,hydrochlorides, hydrobromides, hydroiodides, 2-hydroxyethanesulfonates,lactates, maleates, methanesulfonates, 2-naphthalenesulfonates,nicotinates, nitrates, oxalates, pectinates, persulfates,3-phenylpropionates, phosphates, picrates, pivalates, propionates,salicylates, succinates, sulfates, sulfonates (such as those mentionedherein), tartarates, thiocyanates, toluenesulfonates (also known astosylates,) undecanoates, and the like. Additionally, acids which aregenerally considered suitable for the formation of pharmaceuticallyuseful salts from basic pharmaceutical compounds are discussed, forexample, by S. Berge et al, Journal of Pharmaceutical Sciences (1977)66(1)1-19; P. Gould, International J. of Pharmaceutics (1986) 33201-217; and Anderson et al, The Practice of Medicinal Chemistry (1996),Academic Press, New York). These disclosures are incorporated herein byreference thereto.

[0139] Exemplary basic salts include ammonium salts, alkali metal saltssuch as sodium, lithium, and potassium salts, alkaline earth metal saltssuch as calcium and magnesium salts, salts with organic bases (forexample, organic amines) such as benzathines, dicyclohexylamines,hydrabamines (formed with. N,N-bis(dehydroabietyl)ethylenediamine),N-methyl-D-glucamines, N-methyl-D-glucamides, t-butyl amines, and saltswith amino acids such as arginine, lysine and the like. Basicnitrogen-containing groups may be quarternized with agents such as loweralkyl halides (e.g. methyl, ethyl, propyl, and butyl chlorides, bromidesand iodides), dialkyl sulfates (e.g. dimethyl, diethyl, dibutyl, anddiamyl sulfates), long chain halides (e.g. decyl, lauryl, myristyl andstearyl chlorides, bromides and iodides), aralkyl halides (e.g. benzyland phenethyl bromides), and others.

[0140] All such acid salts and base salts are intended to bepharmaceutically acceptable salts within the scope of the invention andall acid and base salts are considered equivalent to the free forms ofthe corresponding compounds for purposes of the invention.

[0141] Compounds of formula I, and salts, solvates and prodrugs thereof,may exist in their tautomeric form (for example, as an amide or iminoether). All such tautomeric forms are contemplated herein as part of thepresent invention.

[0142] All stereoisomers (for example, geometric isomers, opticalisomers and the like) of the present compounds (including those of thesalts, solvates and prodrugs of the compounds as well as the salts andsolvates of the prodrugs), such as those which may exist due toasymmetric carbons on various substituents, including enantiomeric forms(which may exist even in the absence of asymmetric carbons), rotamericforms, atropisomers, and diastereomeric forms, are contemplated withinthe scope of this invention. Individual stereoisomers of the compoundsof the invention may, for example, be substantially free of otherisomers, or may be admixed, for example, as racemates or with all other,or other selected, stereoisomers. The chiral centers of the presentinvention can have the S or R configuration as defined by the IUPAC 1974Recommendations. The use of the terms “salt”, “solvate” “prodrug” andthe like, is intended to equally apply to the salt, solvate and prodrugof enantiomers, stereoisomers, rotamers, tautomers, racemates orprodrugs of the inventive compounds.

[0143] When a variable appears more than once in the structural formula,for example R³ or R⁵, the identity of each variable appearing more thanonce may be independently selected from the definition for thatvariable.

[0144] The compounds of the present invention can have pharmacologicalproperties, for example the compounds of Formula I can be inhibitors ofTACE (TNF-α) and/or MMP activity. The compounds of Formula I can haveanti-inflammatory activity and/or immunomodulatory activity and can beuseful in the treatment of diseases including but not limited to septicshock, haemodynamic shock, sepsis syndrome, post ischaemic reperfusioninjury, malaria, mycobacterial infection, meningitis, psoriasis,congestive heart failure, fibrotic diseases, cachexia, graft rejection,cancers such as cutaneous T-cell lymphoma, diseases involvingangiogenesis, autoimmune diseases, skin inflammatory diseases,inflammatory bowel diseases such as Crohn's disease and colitis, osteoand rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis,adult Still's disease, ureitis, Wegener's granulomatosis, Behcehedisease, Sjogren's syndrome, sarcoidosis, polymyositis, dermatomyositis,multiple sclerosis, radiation damage, hyperoxic alveolar injury,periodontal disease, HIV, non-insulin dependent diabetes mellitus,systemic lupus erythematosus, glaucoma, sarcoidosis, idiopathicpulmonary fibrosis, bronchopulmonary dysplasia, retinal disease,scleroderma, osteoporosis, renal ischemia, myocardial infarction,cerebral stroke, cerebral ischemia, nephritis, hepatitis,glomerulonephritis, cryptogenic fibrosing aveolitis, psoriasis,transplant rejection, atopic dermatitis, vasculitis, allergy, seasonalallergic rhinitis, reversible airway obstruction, adult respiratorydistress syndrome, asthma, chronic obstructive pulmonary disease (COPD)and/or bronchitis. It is contemplated that a compound of this inventionmay be useful in treating one or more of the diseases listed.

[0145] Additionally, a compound of the present invention may beco-administered or used in combination with disease-modifyingantirheumatic drugs (DMARDS) such as methotrexate, azathioprine,leflunomide, pencillinamine, gold salts, mycophenolate mofetil,cyclophosphamide and other similar drugs. They may also beco-administered with or used in combination with NSAIDS such aspiroxicam, naproxen, indomethacin, ibuprofen and the like; COX-2selective inhibitors such as Vioxx® and Celebrex®; immunosuppressivessuch as steroids, cyclosporin, Tacrolimus, rapamycin and the like;biological response modifiers (BRMs) such as Enbrel®, Remicade®, IL-1antagonists, anti-CD40, anti-CD28, IL-10, anti-adhesion molecules andthe like; and other anti-inflammatory agents such as p38 kinaseinhibitors, PDE4 inhibitors, other chemically different TACE inhibitors,chemokine receptor antagonists, Thalidomide: and other small moleculeinhibitors of pro-inflammatory cytokine production.

[0146] Also, a compound of the present invention may be co-administeredor used in combination with an Hi antagonist for the treatment ofseasonal allergic rhinitis and/or asthma. Suitable Hi antagonists maybe, for example, Claritin®, Clarinex®, Allegra®, or Zyrtec®.

[0147] In another aspect, the invention provides a method for treatingrheumatoid arthritis comprising administering a compound of the formulaI in combination with compound selected from the class consisting of aCOX-2 inhibitor e.g. Celebrex® or Vioxx®; a COX-1 inhibitor e.g.Feldene®; an immunosuppressive e.g. methotrexate or cyclosporin; asteroid e.g. β-methasone; and anti-TNF-α compound, e.g. Enbrel® orRemicade®; a PDE IV inhibitor, or other classes of compounds indicatedfor the treatment of rheumatoid arthritis.

[0148] In another aspect, the invention provides a method for treatingmultiple sclerosis comprising administering a compound of the formula Iin combination with a compound selected from the group consisting ofAvonex®, Betaseron, Copaxone or other compounds indicated for thetreatment of multiple sclerosis.

[0149] TACE activity is determined by a kinetic assay measuring the rateof increase in fluorescent intensity generated by TACE catalyzedcleavage of an internally quenched peptide substrate (SPDL-3). Thepurified catalytic domain of recombinant human TACE (rhTACEc, Residue215 to 477 with two mutation (S266A and N452Q) and a 6×His tail) is usedin the assay. It is purified from the baculovirus/Hi5 cells expressionsystem using affinity chromatography. The substrate SPDL-3 is aninternally quenched peptide(MCA-Pro-Leu-Ala-Gln-Ala-Val-Arg-Ser-Ser-Ser-Dpa-Arg-NH2), with itssequence derived from the pro-TNFα cleavage site. MCA is(7-Methoxycoumarin-4-yl)acetyl. Dpa isN-3-(2,4-Dinitrophenyl)-L-2,3-diaminopropionyl.

[0150] A 50 μl assay mixture contains 20 mM HEPES, pH 7.3, 5 mM CaCl₂,100 μM ZnCl₂, 2% DMSO, 0.04% Methylcellulose, 30 μM SPDL-3, 70 pMrhTACEc and a test compound. RhTACEc is pre-incubated with the testingcompound for 90 min. at 25° C. Reaction is started by addition of thesubstrate. The fluorescent intensity (excitation at 320 nm, emission at405 nm) was measured every 45 seconds for 30 min. using afluorospectrometer (GEMINI XS, Molecular Devices). Rate of enzymaticreaction is shown as Units per second. Effect of a test compound isshown as % of TACE activity in the absence of the compound.

[0151] Useful compounds for TACE inhibitory activity can exhibit K_(i)values of less than about 1000 nm, preferably about 0.01 nm to about1000 nm, more preferably about 0.1 nm to about 100 nm, more preferablyabout 0.1 to about 15 nm, and most preferably less that about 15 nm.Representative compounds of the invention which exhibit excellent TACEinhibitory activity (K_(i) values of less than about 20 nanomolar, nm)are as follows: Compounds BX, JH, BD, BW, KM, BL, O, P, JY, JX, CV, CA,JG, BV, CC, JO, CP, JN, CT, FQ, DE, FN, KX, LB, IZ, GV, JB, JA, LA, KY,BY, JD, BO, BP, DA, FG, CU, CW, LC, JF, DB, CS, JC, JE, KZ, CO, JT, JU,JS, JR, FY, CR, GA, GB, CY, JV, BR, CZ, FZ, BQ, CQ, FX, FU, FW, JW, FV,CN, CA, JP, BS, LM, LI and LH. The Compound letter designations refer tothe letter designations for the various structures in Table 1 in theEXAMPLES section found below.

[0152] The pharmaceutical compositions containing the active ingredientmay be in a form suitable for oral use, for example, as tablets,lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsions, hard or soft capsules, or syrups or elixirs. Compositionsintended for oral use may be prepared according to any method known tothe art for the manufacture of pharmaceutical compositions and suchcompositions may contain one or more agents selected from the groupconsisting of sweetening agents, flavoring agents, coloring agents andpreserving agents in order to provide pharmaceutically elegant andpalatable preparations. Tablets contain the active ingredient inadmixture with non-toxic pharmaceutically acceptable excipients that aresuitable for the manufacture of tablets. These excipients may be forexample, inert diluents, such as calcium carbonate, sodium carbonate,lactose, calcium phosphate or sodium phosphate; granulating anddisintegrating agents, for example, corn starch, or alginic acid;binding agents, for example starch, gelatin or acacia, and lubricatingagents, for example magnesium stearate, stearic acid or talc. Thetablets may be uncoated or they may be coated by known techniques todelay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distearatemay be employed. They may also be coated by the technique described inthe U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotictherapeutic tablets for controlled release.

[0153] Formulations for oral use may also be presented as hard gelatincapsules wherein the active ingredients is mixed with an inert soliddiluent, for example, calcium carbonate, calcium phosphate or kaolin, ora soft gelatin capsules where in the active ingredient is mixed withwater or an oil medium, for example peanut oil, liquid paraffin or oliveoil.

[0154] Aqueous suspensions contain the active material in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example, sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example, lecithin, or condensation products of an alkylene oxidewith fatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample, heptadecaethylene-oxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example, polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample, ethyl or n-propyl, p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose, saccharin or aspartame.

[0155] Oily suspensions may be formulated by suspending the activeingredient in a vegetable oil, for example, arachis oil, olive oil,sesame oil or coconut oil, or in mineral oil such as liquid paraffin.The oily suspensions may contain a thickening agent, for example,beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as thoseset forth above, and flavoring agents may be added to provide apalatable oral preparation. These compositions may be preserved by theaddition of an anti-oxidant such as ascorbic acid.

[0156] Dispersible powders and granules suitable for preparation of anaqueous suspension by the addition of water provide the activeingredient in admixture with a dispersing or wetting agent, suspendingagent and one or more preservatives. Suitable dispersing or wettingagents and suspending agents are exemplified by those already mentionedabove. Additional excipients, e.g., sweetening, flavoring and coloringagents, may also be present.

[0157] The pharmaceutical compositions of the invention may also be inthe form of an oil-in-water emulsions. The oily phase may be a vegetableoil, e.g., olive oil or arachis oil, or a mineral oil, e.g., liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring phosphatides, e.g., soy beans, lecithin, and estersor partial esters derived from fatty acids and hexitol anhydrides, forexample, sorbitan monooleate, and condensation products of the saidpartial esters with ethylene oxide, e.g., polyoxyethylene sorbitanmonooleate. The emulsions may also contain sweetening and flavoringagents.

[0158] Syrups and elixirs may be formulated with sweetening agents, forexample, glycerol, propylene glycol, sorbitol or sucrose. Suchformulations may also contain a demulcent, a preservative and flavoringand coloring agents.

[0159] The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally-acceptable diluent orsolvent, e.g., as a solution in 1,3-butane diol. Among the acceptablevehicles and solvents that maybe employed are water, Ringer's solutionand isotonic sodium chloride. solution. In addition, sterile fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil may be employed including synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectables.

[0160] Compounds of the invention may also be administered in the formof suppositories for rectal administration of the drug. The compositionscan be prepared by mixing the drug with a suitable non-irritatingexcipient which is solid at ordinary temperatures but liquid at therectal temperature and will therefore melt in the rectum to release thedrug. Such materials are cocoa butter and polyethylene glycols.

[0161] For topical use, creams, ointments, jellies, solutions orsuspensions, etc., containing the compound of The invention areemployed. (For purposes of this application, topical application shallinclude mouthwashes and gargles.)

[0162] The compounds for the present invention can be administered inthe intranasal form via topical use of suitable intranasal vehicles, orvia transdermal routes, using those forms of transdermal skin patcheswell known to those of ordinary skill in the art. To be administered inthe form of a transdermal delivery system, the dosage administrationwill, of course, be continuous rather than intermittent throughout thedosage regimen. Compounds of the present invention may also be deliveredas a suppository employing bases such as cocoa butter, glycerinatedgelatin, hydrogenated vegetable oils, mixtures of polyethylene glycolsof various molecular weights and fatty acid esters of polyethyleneglycol.

[0163] The dosage regimen utilizing the compounds of the presentinvention is selected in accordance with a variety of factors includingtype, species, weight, sex and medical condition of the patient; theseverity of the condition to be treated; the route of administration;the renal and hepatic function of the patient; and the particularcompound thereof employed. A physician or veterinarian of ordinary skillcan readily determine and prescribe the effective amount of the drugrequired to prevent, counter, arrest or reverse the progress of thecondition. Optimal precision in achieving concentration of drug withinthe range that yields efficacy without toxicity requires a regimen basedon the kinetics of the drug's availability to target sites. Thisinvolves a consideration of the distribution, equilibrium, andelimination of a drug. Preferably, doses of the compound of Formula Iuseful in the method of the present invention range from 0.01 to 1000 mgper day. Most preferably, dosages range from 0.1 to 500 mg/day. For oraladministration, the compositions are preferably provided in the form oftablets containing 0.01 to 1000 milligrams of the active ingredient,particularly 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0,50.0, 100 and 500 milligrams of the active ingredient for thesymptomatic adjustment of the dosage to the patient to be treated. Aneffective amount of the drug is ordinarily supplied at a dosage level offrom about 0.0002 mg/kg to about 50 mg/kg of body weight per day. Therange is more particularly from about 0.001 mg/kg to 1 mg/kg of bodyweight per day.

[0164] Advantageously, the active agent of the present invention may beadministered in a single daily dose, or the total daily dosage may beadministered in dividend doses of two, three or four time daily.

[0165] The amount of active ingredient that may be combined with thecarrier materials to produce single dosage form will vary depending uponthe host treated and the particular mode of administration.

[0166] It will be understood, however, that the specific dose level forany particular patient will depend upon a variety of factors includingthe age, body weight, general health, sex, diet, time of administration,route or administration, rate of excretion, drug combination and theseverity of the particular disease undergoing therapy.

[0167] The compounds of the invention may be produced by processes knownto those skilled in the art and as shown in the following reactionschemes and in the preparations and examples described below.

EXAMPLES

[0168] The following abbreviations are used in the procedures andschemes: dichloromethane (DCM); tetrabutylammonium bromide (TBAB);Benzyl (Bn); acetonitrile (MeCN); ethyl acetate(EtOAc); Tetrahydrofuran(THF); Trifluoroacetic acid (TFA); 1-hydroxy-7-aza-benzotriazole (HOAt);1-hydroxylbenzotriazole(HOAt); N-methylmorpholine (NMM);1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCl);diisopropylethyl amine (DIEA); 1-hydroxybenzotriazole (HOBt);Dimethoxyethane (DME).[1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate)](Selectfluor); 4-N,N-dimethylaminopyridine(DMAP); 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU); Saturated (sat.);anhydrous. (anhyd); room temperature (rt); hour (h); Minutes (Min),Retention Time (R_(t)); molecular weight (MW); milliliter (mL); gram(g). milligram (mg); equivalent (eq).

[0169] All NMR data were collected on 400 MHz NMR spectrometers unlessotherwise indicated. LC-Electrospray-Mass spectroscopy with a C-18column and 5% to 95% MeCN in water as the mobile phase was used todetermine the molecular mass and retention time.

[0170] The compounds in the invention may be produced by processes knownto those skilled in the art and as shown in the following reactionschemes and in the preparations and examples described below. Table 1contains the compounds with retention time/observed MW and/or NMR data.The compounds of Table 1 can be obtained using synthetic methods similarto those below as listed in the last column of Table 1 using appropriatereagents known to those skilled in the art.

[0171] Synthesis of Compound 2

[0172] To a solution of 50 g (0.28 mol) of compound 1 in 500 mL ofanhyd. DCM in an ice bath was added 560 mL 1 N BBr₃ in DCM. The finalsolution was stirred for 30 min before it was quenched with 200 mL MeOH.After the solvent was evaporated, the residue was dissolved in 500 mL ofDCM, washed with water, sat. NaHCO₃, and brine. The organic phase wasdried over anhyd. sodium sulfate. The solvent was evaporated to give41.5 g of desired compound 2 (90%) which was used in the next stepwithout purification.

[0173] Synthesis of Compound 3

[0174] To a mixture of 41.5 g of Compound 2 in 500 mL DCM, was added 10eq. anhyd. K₂CO₃, 0.05 eq of tetrabutylammonium bromide (TBAB), and 1eq. of benzylbromide. The mixture was stirred overnight, and the solidwas filtered and washed with DCM. The combined organic solution waswashed with water, saturated aqueous Na₂CO₃, brine, and dried overanhyd. sodium sulfate. The solvent was evaporated to give 57.6 g ofcompound 3 (90%), which was used in the next steps without purification.

[0175] Synthesis of Compound 4

[0176] To a solution of 57.6 g of Compound 3 in 500 mL of hexane wasadded K₂CO₃ (10 eq), TBAB (0.05 eq) and paraformaldehyde (20 eq), andthe final mixture was refluxed overnight under effective stirring. Thereaction mixture was partitioned between water and DCM, and the aqueouslayer was extracted with DCM. The combined organic solution was washedwith water, sat. Na₂CO₃, brine, and dried over anhyd. Na₂SO₄. Thesolvent was removed and the residue chromatographed with 1-10%ethylacetate in hexane to give 31 g of compound 4 (51%).

[0177] Synthesis of Compound 5

[0178] To a solution of 31 g of Compound 4 in 500 mL of MeCN was addedS-carbo-tert-butoxymethyl-tetrahydrothiophene bromide (1.1 eq) and DBU(1.5 eq). The solution was stirred overnight and the solvent wasevaporated. The residue dissolved in 500 mL DCM. The organic solutionwas washed with H₂O, 0.1 N HCl, water, brine, and dried over anhyd.Na₂SO₄. After removal of the solvent, the residue was chromatographedwith 1-20% EtOAc/Hexane to give 32 g of compound 5 (73%).

[0179] Synthesis of 6

[0180] A mixture of 100 mL methanol solution of 2.0 g of Compound 5 with200 mg of 10% Pd/C was stirred under H₂ until the starting materialdisappeared. The solution was filtered and the solvent evaporated togive compound 6 in quantitative yield.

[0181] Chiral Resolution of Compound 6

[0182] Compound 6 (1.0 g) was resolved with an OD chiral column elutedwith 5% IPA/Hexane (120 mL/min). The first peak at 19.9 min wascollected as enantiomer 6a and the second peak at 28.17 min wascollected as enantiomer 6b.

[0183] Synthesis of Compound 7

[0184] To a mixture of compound 6 (99 mg, 0.34 mmol), 31 mg of TBAB, 154mg of anhyd K₂CO₃ in 2 mL of anhyd DCM was added 0.06 mL of benzylbromide. The final solution was heated to 40° C. for 3 h. The mixturewas diluted with 50 mL DCM and washed with water before the organiclayer was dried over anhyd Na₂SO₄. The solvent was evaporated to givecompound 7, which was used in the next step without purification.

[0185] Synthesis of Compound 8

[0186] A solution of Compound 7 (100 mg) in 30% TFA in DCM was kept for4 h before the solvent was evaporated. The residue was adjusted topH˜9.5 with a 1:1 ratio of sat. NaHCO₃/Na₂CO₃ and the aqueous solutionwashed with ether. After acidification to pH˜2, the aq layer wasextracted with EtOAc. The combined organic layers were dried and solventremoved to give compound 8, which was used without purification for nextstep.

[0187] Synthesis of Compound 9

[0188] To a DCM solution of compound 8 at 0° C. were added HOAt (47 mg),O-tritylhydroxylamine (284 mg) and NMM 0.23 mL followed by 105 mg EDCl.The final solution was stirred overnight and the reaction mixture wasdiluted with 50 mL DCM and washed with NaHCO₃ and water. The organiclayer was dried over anhyd Na₂SO₄. After removal of solvent the residuewas chromatographed on a silica gel column eluting with 10-40% EtOAc inhexane to give 132 mg of Compound 9.

[0189] Synthesis of Compound 10

[0190] To a 2 mL solution of 60 mg of Compound 9 was added 55 mg oftriethylsilane followed by 230 mg of TFA. The solution was evaporatedand the residue was purified through a C-18 reverse phase HPLC columneluting with 5-95% of acetonitrile in water to give 32 mg of Compound 20as a white solid.

[0191]¹H NMR (CD₃CN) of 10: δ 7.6-7.4 (m, 5H); 7.3 (m, 1H); 6.95 (m,3H); 5.2 (m, 2H); 3.7 (s, 3H); 2.6 (m, 1H); 2.05 (m, 1H); 1.85 (m, 1H).

[0192] Synthesis of Compound 11

[0193] A solution 150 mg of Compound 9 and 1 g of LiOH.H₂O in a mixtureof 20 mL MeOH, 10 mL THF and 10 mL H₂O was refluxed for 30 min. Thesolvent was evaporated and the residue was dissolved in a mixture of 100mL DCM/100 mL of sat. aq ammonium chloride. The organic layer wasseparated, dried over anhyd sodium sulfate, and the solvent evaporatedto give 150 mg of 11.

[0194] Synthesis of Compound 11a

[0195] Compound 11 was dissolved in 2 ml of DMF followed by addition of6 eq. of ammonium chloride, 2.5 eq. of HOBt, 25 eq of DIEA and 2.5 eq ofEDCl. The mixture was stirred overnight followed by dilution with DCMand washed with water. The organic layer was dried over anhyd. sodiumsulfate and the solvent was evaporated. The residue was chromatographedwith a silica gel column to give 106 mg of Compound 11a.

[0196] Synthesis of Compound 12

[0197] Compound 12 was synthesized from 11a following a proceduresimilar to the transformation from 9 to 10 (Method 2).

[0198]¹H NMR(CDCl₃) of 12: δ 7.4-7.6 (m, 5H); 7.29 (m, 1H); 7.05 (m,3H); 6.4 (br. s, 1H); 5.85 (br. s, 1H); 5.2 (m, 2H); 2.59 (m, 1H); 1.9(m, 1H); 1.75 (m, 1H).

[0199] Synthesis of Compound 14

[0200] Compound 14 was synthesized from 13 following procedures similarto the transformation from 3 to 6 (Method 1).

[0201] Synthesis of Compound 15

[0202] Compound 15 was synthesized from 14 following procedures similarto the transformation from 6 to 10 (Method 2).

[0203]¹H NMR(CD₃CN) of 15: δ 7.45-7.62 (m, 5H); 7.3 (m, 2H); 7.01 (m,2H); 5.2 (s, 2H); 4.18 (m, 2H); 2.6 (m, 1H); 2.02 (m, 1H); 1.85 (m, 1H);1.23 (m, 3H).

[0204] Synthesis of Compound 17

[0205] To a solution of 10.5 g of Compound 16 (40 mmol) in 100 mL ofanhyd THF at −78° C. was added 53 mL of 1.5 M tert-Butyllithium inhexane over 5 min. After the solution was stirred at −78° C. for 1 h, itwas added into a mixture of CuCN (40 mmol) in 20 mL of THF at 0° C. Thesolution was stirred for 30 min before it was cooled to −78° C. andadded to a solution of methyl 2-(bromomethyl)acrylate (29 mmol) in 20 mLof THF at −78° C. The reaction was stirred for 30 min at −78° C.followed by warming to −10° C. for 10 min before it was poured into amixture of saturated NH₄Cl in ice. The mixture was extracted with DCMand the residue chromatographed with 10% EtOAc/Hexane to give 6.0 g ofthe desired product 17.

[0206]¹H NMR (CDCl₃) of 17: δ 7.5-7.3 (m, 5H); 7.13 (d, 2H); 6.94 (d,2H); 6.22 (br s, 1H); 5.47 (br s, 1H); 5.05 (s, 2H); 3.75 (s, 3H); 3.59(s, 2H).

[0207] Synthesis of Compound 18

[0208] Compound 18 was synthesized from 17 following a procedure similarto the transformation from 4 to 5 (Method 1).

[0209] Synthesis of Compound 19

[0210] Compound 19 was synthesized from 18 following a procedure similarto the transformation from 5 to 6 (Method 1).

[0211] Chiral Resolution of 19

[0212] Methods similar to the resolution of Compound 6 were used for theresolution of Compound 19. The first enantiomer was collected as 19a andthe second enantiomer collected as 19b.

[0213] Synthesis of Compound 19c

[0214] Compound 19c was synthesized from 19a following a proceduresimilar to the transformation from 7 to 8 (Method 2).

[0215] Synthesis of Compound 20

[0216] Compound 20 was synthesized from 18 following a procedure similarto the transformation of 7 to 8 (Method 2).

[0217] Synthesis of Compound 21

[0218] A solution of acid 20 (0.190 mg, 0.56 mmol), Wang hydroxylamineresin (0.500 g, 1 mmol/g), EDCl (0.172 g, 0.90 mmol), NMM (0.400 mL,3.64 mmol), and HOAt (0.075 g, 0.55 mmol) in DCM (7 mL) was agitated for14 hours at room temperature. The liquid was drained, and the resin waswashed with CH₂Cl₂ (3×), THF(3×), and MeOH(3×) in an alternatingsequence. The resin was dried under high vacuum to yield resin 21 (0.630g, 0.79 mmol/g).

[0219] Synthesis of Compound 22

[0220] A mixture of resin 21 (0.067 g, 0.79 mmol/g) and 1M Bu₄NOH in THF(2 mL) was agitated at 60° C. for 4 h. The liquid was drained and theresin was washed with 1% AcOH in DMF (2×30 min.) followed by analternating cycle of washes with MeOH (3×), THF (3×) and CH₂Cl₂ (3×).The resulting resin was dried under high vacuum for 4 hours.

[0221] A mixture of the carboxylic acid resin prepared above (0.067 g,0.79 mmol/g), EDCl (0.045 g, 0.23 mmol), HOBt (0.030 g, 0.20 mmol) andNMM (0.026 mL, 0.24 mmol) in NMP (2 mL) was agitated for 20 minutesbefore the addition of benzyl amine (0.026 mL, 0.24 mmol). This mixturewas agitated for 18 hours at rt. The liquid was drained, and the resinwas washed with an alternating cycle of CH₂Cl₂ (3×), THF (3×), and MeOH(3×). The remaining resin was treated with 50% TFA/CH₂Cl₂ (2 mL) andagitated for 1 hour. The liquid was drained, and the remaining resin waswashed with CH₂Cl₂ (2×). Concentration of the liquid afforded Compound22 (10 mg, 0.023 mmol).

[0222]¹H NMR (CD₃CN/D₂O, 2:1) of 22: δ 7.29-7.44 (m, 6H), 7.14-7.07 (m,4H), 6.84-6.81 (m, 4H), 5.03 (s, 2H), 4.22-4.13 (m, 2H), 3.12-2.93 (m,2H), 2.07-2.03 (m, 1H), 1.49-1.46 (m, 1H), 1.40-1.38 (m, 1H).

[0223] Synthesis of Compound 23

[0224] To a solution of compound 19a (0.04 g) and4-chloromethyl-2-methylquinoline (1.5 eq) in 1 mL of DMF was added 0.25g of potassium carbonate and 20 mg of tetrabutylammonium iodide. Themixture was stirred overnight before it was partitioned in a mixture ofDCM/water. The aqueous layer was extracted twice with DCM and thecombined organic layer was dried and solvent removed. The residue waschromatographed to give compound 23 (0.08 g).

[0225] Synthesis of Compound 24

[0226] Compound 24 was synthesized from 23 following a procedure similarto the transformation of 7 to 8 (Method 2).

[0227] Synthesis of Compound 25

[0228] Compound 25 was synthesized from 24 following a procedure similarto the transformation of 8 to 9 (Method 2).

[0229] Synthesis of Compound 26

[0230] Compound 26 was synthesized from 25 following a procedure similarto the transformation of 9 to 10 (Method 2).

[0231]¹H NMR (CD₃CN/D₂O, 2:1) of 26: δ 8.38 (m, 1H), 8.28 (m, 1H), 8.05(m, 1H). 8.01 (s, 1H); 7.88 (m, 1H); 7.20 (m, 2H); 7.04 (m, 2H); 5.71(s, 2H), 3.57 (s, 3H), 2.96-3.4 (m, 2H), 2.95 (s, 3H); 2.23 (m, 1H),1.49-1.46 (m, 2H).

[0232] Synthesis of Compound 25a

[0233] Compound 25a was synthesized from 25 using a procedure similar tothe transformation of 9 to 11 (Method 3).

[0234] Synthesis of Compound 27a

[0235] To a solution of acid 25a (0.043 g, 0.067 mmol) in CH₂Cl₂ (1 mL)at room temperature was added DMAP (0.025 mg, 0.20 mmol) and EDCl (0.033g, 0.17 mmol). This mixture was stirred for 25 minutes and 2-propanol(0.20 mL, 2.6 mmol) was then added. The resulting mixture was stirredfor 16 hours. The reaction was quenched with H₂O and diluted with ethylacetate. The organic phase was removed, and the aqueous layer wasextracted with ethyl acetate (3×). The combined organic layers werewashed with H₂O (2×), brine (1×), dried (Na₂SO₄), filtered, andconcentrated. The residue was purified by flash chromatography to affordcompound 27a.

[0236]¹H NMR (CD₃OD): δ 8.4 (m, 1H), 8.05-8.02 (m, 3H), 7.93 (m, 1H),7.25 (m, 2H); 7.05 (m, 2H); 5.8 (s, 2H), 4.88 (m, 1H); 3.0-3.24 (m, 2H),2.96 (s, 3H); 2.24 (m, 1H); 1.5 (m, 2H); 1.1 (m, 6H).

[0237] Synthesis of Compound 27b

[0238] Compound 27b was synthesized from 25a following proceduressimilar to the transformation of 11 to 12 (Method 3).

[0239]¹H NMR (CD₃OD) of 27b: δ 8.12 (m, 1H), 8.01 (m, 1H), 7.80 (m, 1H),7.62 (m, 2H); 7.23 (m, 2H); 7.01 (m, 2H); 5.57 (s, 2H), 3.1-3.3 (m, 2H);2.74 (s, 3H); 2.14 (m, 1H), 1.54 (m, 1H); 1.46 (m, 1H).

[0240] Synthesis of 28

[0241] Compound 28 was synthesized from 16 following procedures similarto the transformation of 16 to 19 (Method 5).

[0242] Synthesis of 29

[0243] Compound 28 was synthesized following a procedure similar to thetransformation of 7 to 8 (Method 2).

[0244] Chiral Resolution of 29

[0245] Compound 29 was resolved with a Chiralpak AS column eluting with40% iPrOH/hexanes (0.1% AcOH) at 70 mL/min. The first peak at wascollected as enantiomer 29a and the second peak was collected asenantiomer 29b.

[0246] Synthesis of Compound 30

[0247] To a methanolic solution of 29a (0.5 g) was added 6 drops ofsulfuric acid and the solution was refluxed for 1 h. After removal ofmethanol, the residue was partitioned in a mixture of DCM/water. Thewater layer was extracted with DCM (3×) and the combined organic layerwas dried and solvent evaporated to give 0.51 g of product 30.

[0248] Synthesis of Compound 31

[0249] Compound 31 was synthesized from 30 following a procedure similarto the transformation of 6 to 7 (Method 2) or 19a to 23 (Method 7).

[0250] Synthesis of Compound 32

[0251] To a solution of Compound 31 (0.08 g) in 4 mL of methanol wasadded 100 mg LiOH in 1 mL of water. The suspension was stirred for 2h atrt and the solution was partitioned in a mixture of DCM/saturatedammonium chloride. The aqueous layer was extracted with DCM and thecombined organic layer was dried and solvent removed to give 75 mg ofcrude 32 which was used for next step without purification.

[0252] Synthesis of Compound 33

[0253] Compound 33 was synthesized from 32 following procedures similarto the transformation from 8 to 10 (Method 2).

[0254]¹H NMR (CD₃CN/D₂O, 2:1): δ 8.07-8.18 (m, 5H), 7.8 (m, 1H), 7.60(m, 1H), 7.5 (m, 3H); 7.23 (m, 2H); 7.01 (m, 2H); 5.57 (m, 2H), 3.97 (m,2H); 2.9-3.2 (m, 2H); 2.2 (m, 1H); 1.5 (m, 2H); 1.1 (m, 3H).

[0255] Synthesis of Compound 34

[0256] Compound 34 was synthesized from 32 following a procedure similarto the transformation from 8 to 9 (Method 2) and then 9 to 12 (Method3).

[0257]¹H NMR (CD₃OD) of 34: δ 8.3-8.5 (m, 3H), 8.05-8.15 (m, 3H),7.85-7.97 (m, 1H), 7.62-7.76 (m, 3H); 7.26 (m, 2H); 7.10 (m, 2H); 5.8(s, 2H), 3.1-3.3 (m, 2H); 2.14 (m, 1H), 1.54 (m, 1H); 1.46 (m, 1H).

[0258] Synthesis of Compound 37

[0259] A solution of 11.5 g of 35 (7.4 mmol), 36 (1 eq) andDiisopropylethylamine (1.5 eq) in 200 mL Acetonitrile was refluxed for 3h. After removing all the solvent, the solid (37, 22 g) was used fornext step without purification.

[0260] Synthesis of Compound 38

[0261] A solution of compound 37(22 g) and 300 mL of 20% hydrazinemonohydrate in methanol was refluxed for 20 minutes. After removal ofthe solvents, the solid was partitioned between 1N NaOH and DCM. The aqlayer was extracted with DCM (×3) before the combined organic layerswere dried and evaporated to give 9.5 g crude product. The hydroxylaminewas mixed with 9.0 g of 2,4-dimethoxybenzaldehyde, 10 g of sodiumacetate in 200 mL of acetic acid. After the mixture was refluxed for 2h, white precipitates formed upon cooling of the reaction. After removalof the solvent, the content was dissolved into DCM and the organic phasewas washed with water. After removal of solvent, the solid wasrecrystalized from MeOH to give 11 g of 38 as a white solid.

[0262] Synthesis of Compound 39

[0263] To a solution of compound 38 (11 g, 36 mmol) in 200 mL aceticacid was added sodium cyanoborohydride (4 eq). The reaction was stirredfor 30 min, and after removal of solvents, the solid was partitionedbetween saturated sodium carbonate/DCM and the aqueous layer wasextracted with DCM (3×). The combined organic layers was dried andevaporated. The residue was chromatographed with a silica gel columnusing ethyl acetate in hexane as elutant to give 9.5 gram crude product39.

[0264] Synthesis of Compound 41

[0265] Compound 41 was synthesized from 40 following a procedure similarto the transformation from 2 to 3 (Method 1).

[0266] Synthesis of Compound 42

[0267] Compound 42 was synthesized from 41 following procedures similarto the transformation from 16 to 19 (Method 5).

[0268] Synthesis of Compound 43

[0269] Compound 43 was synthesized from 42 following a procedure similarto the transformation from 7 to 8 (Method 2).

[0270] Chiral Resolution of 43

[0271] Compound 43 was resolved with a procedure similar to theresolution of compound 29. The first peak at was collected as enantiomer43a and the second peak was collected as enantiomer 43b.

[0272] Synthesis of Compound 44

[0273] Compound 44 was synthesized from 43a following a proceduresimilar to the transformation from 29 to 30 (Method 9).

[0274] Synthesis of Compound 45

[0275] To a cooled solution of compound 43 (5.5 g, 20.5 mmol), DMAP (1mmol), diisopropylethylamine (2.0 eq) in 40 mL anhyd. DCM at 0° C. wasadded acetyl chloride. The starting material disappeared in 30 min andthe reaction mixture was washed with 0.5 N HCl. After removal ofsolvent, the residue was dissolved in 30 mL of anhyd. DCM followed byaddition of oxalyl chloride (3 eq) and 2 drops of DMF. The reaction waskept overnight under rt and solvent evaporated to give a crude product45 as an oil, which was used for next step without further purification.

[0276] Synthesis of Compound 47

[0277] After evaporating solvent from the DCM solution of 45 threetimes, the crude acid chloride was dissolved in 20 mL of DCM followed byaddition of a 5 mL DCM solution of compound 39 with 2 eq ofdiisopropylethylamine. After the solution was stirred overnight at rt,the solvent was evaporated to give the crude product 46. After the crudeproduct was treated with 7N ammonia in methanol for 30 min, the solventwas removed and the residue chromatographed on a silica gel columneluted with ethyl acetate and hexane to give 5.1 g of product 47.

[0278] Synthesis of Compound 48

[0279] Compound 48 was synthesized from compound 47 following aprocedure similar to the transformation from 9 to 11 (Method 3).

[0280] Synthesis of Compound 49

[0281] Compound 49 was synthesized from compound 48 following proceduressimilar to the transformation from 11 to 11 (Method 3).

[0282] Synthesis of Compound 50a

[0283] Compound 50a was synthesized following a procedure similar to thetransformation from 30 to 31 (Method 10).

[0284] Synthesis of Compound 51b

[0285] Compound 50a (98 mg, 2 mmol) was dissolved in MeOH andhydroxylamine hydrochloride (440 mg, 6.3 mmol) and DBU (1.76 mL, 11.8mmol) were added. The reaction mixture was stirred at rt for 2 h. AcOH(680 μL, 11.8 mmol) was added and the reaction mixture was concentratedto dryness. The crude product was purified via silica gel chromatographyusing 95:5 CH₂Cl₂:MeOH as the mobile phase to give 12 mg of 51b.

[0286]¹H NMR (300 MHz, CDCl₃): δ 7.90 (m, 1H), 7.80 (m, 1H), 7.63 (s,1H), 7.58-7.50 (m, 1H), 7.46-7.43 (m, 1H), 6.89 (m, 2H), 6.64 (m, 2H),5.28 (s, 2H), 3.73-3.70 (m, 2H), 2.98 (s, 2H), 1.92 (m, 1H), 1.25-1.21(m, 2H), 0.81 (m, 3H).

[0287] Synthesis of Compound 52

[0288] To a mixture of compound 51 (0.5 gram) in 30 mL of methanol wasadded sulfuric acid (1.5 eq) and the mixture was refluxed for 6 h. Afterremoval of the solvent, the residue was dissolved in DCM and thesolution was washed with sat sodium bicarbonate. The organic layer wasdried and solvent evaporated to give 0.5 g of product 52, which was usedwithout purification for next step.

[0289] Synthesis of Compound 53

[0290] To a solution of compound 52 (0.5 gram) in 20 mL of methanol wasadded sodium borohydride (2 eq), and the mixture was stirred overnight.After the removal of solvent, the residue was partitioned in DCM andwater. The aqueous layer was extracted(3×) and the combined organiclayer was dried, solvent evaporated to give compound 53 (0.45 g) whichwas used for next step without purification.

[0291]¹H NMR (CDCl₃) δ 7.96 (d, 1 H); 7.81 (d, 1 H); 7.61 (m, 1 H); 7.41(m, 1 H); 7.21 (s, 1 H); 5.13 (s, 2H); 2.20 (m, 1H); 1.06 (m, 4 H).

[0292] Synthesis of Compound 54

[0293] To a solution of compound 53 (0.5 gram) in 20 mL of anhyd. DCMwas added thionyl chloride (2 eq), and the mixture was stirred for 30min. After removal of solvent, the residue was partitioned in DCM andwater. The aqueous layer was extracted(3×) and the combined organiclayer was dried, solvent evaporated to give compound 54 (0.55 g) whichwas used for next step without purification.

[0294] Synthesis of Compound 55

[0295] To a 1 mL DMF solution of 20 mg of 49 (0.036 mmol), 9 mg of 54 asa HCl salt (0.035 mmol) and 2 mg of tetrabutylammonium iodide was addedwith 200 mg of potassium carbonate and the mixture was stirredovernight. After removal of DMF, the residue was chromatographed to give23 mg of product 55.

[0296] Synthesis of Compound 56

[0297] To a solution of compound 55 in 1 mL of DCM was added 5 eq oftriethylsilane and 1 mL TFA. The solution was let stand for 2 h and thesolvent evaporated. The residue was chromatographed with a C-30 reversephase HPLC eluted with 5-95% acetonitrile in water to give 15 mg of 56.

[0298]¹H NMR (CD₃OD): δ 8.08 (m, 1H); 7.95 (m, 1H); 7.75 (m, 1H); 7.55(m, 1H); 7.4 (s, 1H); 7.0-7.2 (m, 3H); 5.6(s, 2H); 3.1-3.3 (m, 2H); 2.3(m, 1H); 2.15(m, 1H); 1.55(m, 1H); 1.45(m, 1H); 1.05-1.2 (m, 4H).

[0299] Synthesis of Compound 57

[0300] Compound 57 was synthesized following procedures similar to thetransformation of 49 to 56 (Method 17).

[0301]¹H NMR (CD₃OD): δ 8.08 (m, 1H); 7.95 (m, 1H); 7.75 (m, 1H); 7.55(m, 1H); 7.4 (s, 1H); 7.0-7.2 (m, 3H); 5.6(s, 2H); 3.61 (s, 3H);3.0-3.25 (m, 2H); 2.3 (m, 2H); 1.55 (m, 2H); 1.05-1.2 (m, 4H).

[0302] Synthesis of Resin 60

[0303] The mixture of 8.3 gram pre-swelled resin 58 (0.91 mmol/g) and1.1 eq of 59 as a HCl salt in 20 mL of 10:20:70 solvent mixture ofHOAc:MeOH:THF was agitated overnight. After the resin was washed withMeOH, THF and DCM, it was preswelled in 20 mL anhyd. DCM. After themixture was cooled down to 0° C., 15 equivalent of BH₃.Py and 23 eq ofdichloroacetic acid were added. After the reaction was agitatedovernight, the resin was washed with MeOH, THF and DCM and dried invacuo to give resin 60.

[0304] Synthesis of Compound 61

[0305] Compound 61 was synthesized following procedures similar to thetransformation from 43 to 45 (Method 13).

[0306] Synthesis of resin bound compound 62

[0307] Compound 61 (150 mg, 0.46 mmol) was dissolved in 2 mL of anhydDCM and the solution was added to 178 mg of resin 60 with 0.2 mL ofDIEA. The final mixture was agitated for 12 h before the resin waswashed with 20% piperidine in DMF followed by wash with combination ofMeOH, DCM and THF. The loading level of the final resin was determinedto be 0.4 mmol/g after cleavage with 75% TFA in DCM overnight.

[0308] Synthesis of Resin Bound Compound 63b and 63c.

[0309] To preswelled resin 62 (75 mg) with anhyd THF was added 5 eq of1,1′-(azodicarboxyl)dipiperidine, 5 eq of 2-3-dichlorobenzylalcohol and7 eq. of tributylphosphine in 3 mL of THF under nitrogen. The finalreaction mixture was heated to 70° C. with agitation overnight. Afterwashing with MeOH, DCM and THF, the resin was cleaved with 75% TFA inDCM for 2 h. The residue after removal of the solvent was purified witha C-18 reverse phase column eluted with 5-95% of MeCN in water to givedesired products 63b and 63c.

[0310]¹H NMR (CD₃OD) for 63b: δ 7.36-7.43 (m, 4H); 7.14-7.17 (m, 2H);6.86-6.88 (m, 2H); 5.03 (2H, s); 3.61 (3H, s); 2.96-3.20 (2H, m);2.23-2.27 (1H, m); 1.52-1.54 (2H, m).

[0311]¹H NMR (CD₃OD) for 63c: δ 7.17-7.23 (m, 4H); 6.89-6.93 (m, 2H);6.65-6.67 (m, 1H); 3.87 (s, 2H); 3.54 (3H, s); 2.86-3.12 (2H, m)2.18-2.22 (1H, m); 1.47-1.49 (2H, m).

[0312] Synthesis of Compound 64

[0313] To pre-swelled resin 62 (75 mg) was added 100 mg 5 micron 4 Åmolecular sieves, 2 eq. of anhyd. copper acetate, and 5 eq of1-naphthylboronic acid followed by 2 mL of anhyd. DCM. The reactionmixture was agitated at rt overnight and the resin washed with THF. Theabove procedure was repeated before the resin was washed with MeOH, DCM,THF, and cleaved with 75% TFA in DCM for 2 h. After removal of organicsolvent, the residue was purified with a C-18 reverse phase columneluted with 5-95% MeCN in water to give 4 mg of desired product 64.

[0314]¹H NMR (CD₃OD): δ 8.1 (m, 1H); 7.85 (m, 1H); 7.6 (m, 1H); 7.5 (m,2H); 7.37 (m, 1H); 7.23 (m, 2H); 6.95 (m, 2H); 6.86 (m, 1H); 4.07(m,2H); 3.1-3.3 (m, 2H); 2.23 (m, 1H); 1.55 (m, 2H); 1.16 (m, 3H).

[0315] Synthesis of Compound 65

[0316] Compound 65 was synthesized from 19 following procedures similarto transformation from compound 9 to 11a (Method 3)

[0317] Synthesis of Compound 66

[0318] Compound 66 was synthesized from 65 following a procedure similarto transformation from compound 2 to 3 (Method 1) or 19a to 23 (Method7).

[0319] Synthesis of Compound 67 and 68

[0320] Lawesson's reagent (250 mg, 0.62 mmol) was added to amide 66 (544mg, 1.2 mmol) in toluene and the reaction was refluxed for an hourbefore another 0.5 equiv of Lawesson's reagent was added. The reactionwas heated for one more hour and the mixture was diluted with DCM,washed with a saturated sodium bicarbonate(3×) and water(3×). Theorganic extract was dried over sodium sulfate and concentrated. Thecrude material was purified via flash chromatography eluting with a 0-2%2N NH₃/CH₃OH:CH₂Cl₂ gradient affording a 1:4 ratio of thioamide 67 tonitrile 68.

[0321] Synthesis of Compound 69

[0322] Compound 69 was synthesized from 68 following procedures similarto the transformation of 7 to 10 (Method 2).

[0323]¹H NMR (CD₃OD): δ 8.45 (m, 1H); 8.16 (m, 3H); 7.97 (m, 1H) 7.3 (m,2H); 7.15 (m, 2H); 5.87 (s, 2H); 3.09 (s, 2H); 3.07 (s, 3H); 2.25 (m,1H); 1.6 (m, 2H).

[0324] Synthesis of Compound 70

[0325] A 50% aq. chloroacetaldehyde solution (0.100 mL, 0.79 mmol) andpotassium bicarbonate (80 mg, 0.8 mmol) was added to thioamide 67 (74mg, 0.16 mmol) in tetrahydrofuran. The solution was stirred overnight atroom temperature. The reaction was concentrated and the residue waspartitioned between DCM and water. The organic extracts were washed withwater (3×), dried over sodium sulfate and concentrated. The crudematerial was dissolved in DCM (2 mL) with diisopropylethylamine (0.056mL, 0.032 mL) and the solution was cooled to 0° C. beforetrifluoroacetic anhydride (0.040 mL, 0.03 mmol) was added. The reactionwas stirred at room temperature for 1.5 hr before it was concentrated.The residue was dissolved in DCM, washed with a saturatedbicarbonate(3×), and water (3×). The organic extracts were dried oversodium sulfate and concentrated. The crude material was purified viaflash chromatography eluted with 0-3% 2N NH₃ in CH₃OH/CH₂Cl₂ gradient toafford 70.

[0326] Synthesis of Compound 71

[0327] Compound 71 was synthesized following procedures similar to thetransformation of 7 to 10 (Method 2).

[0328]¹H NMR (CD₃OD): δ 8.45 (m, 1H); 8.10 (m, 2H); 8.08 (m, 1H); 7.97(m, 1H) 7.58 (m, 1H); 7.36 (m, 1H); 7.14 (m, 2H); 7.01 (m, 2H); 5.80 (s,2H); 3.3-3.5 (m,); 2.95 (s, 3H); 2.25 (m, 1H); 1.83 (m, 1H); 1.77 (m,1H).

[0329] Synthesis of Compound 72

[0330] Hydroxylamine hydrochloride (186 mg, 2.7 mmol) anddiisopropylethylamine (0.47 mL, 2.7 mmol) were combined in ethanol andagitated for 30 minutes before compound 69 (105 mg, 0.25 mmole) wasadded to the solution. The reaction was irradiated in a microwave forfive minutes at 100° C. followed by addition of 10 eq of bothhydroxylamine hydrochloride and diisopropylethylamine. The reaction wasirradiated with a microwave for five additional minutes at 100° C.before the reaction was concentrated. The residue was dissolved in DCMand washed with a saturated aqueous solution of sodium bicarbonate (3×)and water (3×). The organic extracts were dried over sodium sulfate andconcentrated to afford 113 mg of crude material.Pyridinium-p-toluenesulfonate (63 mg, 0.25 mmol) andtriethylorthoformate (1 mL, 6.0 mmol) were added to the above crudematerial in ethanol followed by irradiation in a microwave for 5 minutesat 100° C. The reaction was concentrated and the resulting oil wasdissolved in DCM, washed with a sat sodium bicarbonate (3×) and water(3×). The organic extracts were dried over sodium sulfate andconcentrated. The crude material was chromatographed with a silica gelcolumn eluted with a 0-3% 2N NH₃ in CH₃OH/CH₂Cl₂ gradient to afford 72.

[0331] Synthesis of Compound 73

[0332] Compound 73 was synthesized from 72 following procedures similarto the transformation of 7 to 10 (Method 2).

[0333]¹H NMR (CD₃OD): δ 9.05 (s, 1H); 8.41 (m, 1H); 8.10 (m, 3H); 7.91(m, 1H); 7.25 (m, 2H); 7.02 (m, 2H); 5.80 (s, 2H); 3.3-3.5 (m,); 2.95(s, 3H); 2.25 (m, 1H); 1.75 (m, 1H); 1.64 (m, 1H).

[0334] Synthesis of Compound 74

[0335] Compound 74 was synthesized from 19a following procedures similarto the transformation from 6b to 9 (Method 2).

[0336] Synthesis of Compound 75

[0337] Compound 75 was synthesized from 74 following procedures similarto the transformation from 9 to 11a (Method 3).

[0338] Synthesis of Compound 76

[0339] Amide 75 (10 mg) was dissolved in 1 mL ofN,N′-dimethylforamide-dimethyl acetal and irradiated with a microwave at100° C. for 5 minutes. After the solution was concentrated, the residuewas dissolved in glacial acetic acid before hydrazine monohydrate wasadded. The reaction was irradiated again with a microwave for 100° C.for 5 minutes and the solution was concentrated. The final productmixture was purified via reverse phase HPLC eluting with a 0-95%CH₃CN/H₂O gradient to give compound 76.

[0340]¹H NMR (CD₃OD): δ 8.35 (m, 1H); 8.7-8.17 (m, 4H); 7.91 (m, 1H);7.10 (m, 2H); 6.98 (m, 2H); 5.76 (s, 2H); 3.3-3.5 (m,); 2.95 (s, 3H);2.08 (m, 1H); 1.68 (m, 2H).

[0341] Synthesis of Compound 77

[0342] Compound 77 was synthesized from 28 following a procedure similarto transformation from compound 2 to 3 (Method 1) or 19 to 23 (Method7).

[0343] Synthesis of Compound 78

[0344] Sodium borohydride (48 mg, 1.3 mmol) was added to a solution of77 (60 mg, 0.13 mmol) in methanol under reflux. Additional amount ofsodium borohydride was added until the starting material is completelyconsumed. After the reaction was concentrated, the residue waspartitioned between DCM and water. The aqueous solution was extractedwith DCM (3×) and the combined organic layers were washed with a sat.solution of NaHCO₃ (3×), H₂O (3×), dried over sodium sulfate. Afterremoval of solvent, the crude material was purified via flashchromatography eluted with ethyl acetate/ hexane to afford 78.

[0345] Synthesis of Compound 79

[0346] Compound 78 was treated with 30% trifluoroacetic acid in DCM (1-2mL) for 2.5 h followed by removal of solvent. The residue was treatedwith 2N NH₃ in methanol followed by removal of solvent. The residue wasused for the synthesis of compound 79 following procedures similar tothe transformation of 8 to 10 (Method 2).

[0347]¹H NMR (CD₃₀OD) of 79: δ 8.35 (m, 1H); 8.13 (m, 1H); 8.01 (m, 1H);7.96 (s, 1H); 7.84 (m, 1H); 7.21 (m, 2H); 7.05 (m, 2H); 5.76 (s, 2H);3.2-3.3 (m,); 2.93 (m, 5H); 1.54 (m, 1H); 1.29 (m, 1H); 0.96 (m, 1H).

[0348] Synthesis of Compound 80 and 81

[0349] To a 2 mL solution of 0.264 g (1 mmol) of 29 was addedN-chlorosuccinate (1.1 eq) and the solution was stirred for 2 h. Afterremoval of solvent, the product mixture was purified via a C-18 reversephase column eluted with 5-95% acetonitrile in water get pure 0.20 g of80 and 0.05 g of 81.

[0350] Synthesis of Compound 82

[0351] Compound 82 was synthesized from 81 following a procedure similarto transformation from 29 to 30 (Method 9) and 30 to 33 (Method 10).

[0352]¹H NMR (CDCl₃): δ 8.10 (m, 1 H); 7.85 (m, 1H); 7.70 (m, 1H); 7.54(m, 1H); 7.26 (m, 2H); 6.98 (m, 1H); 6.71 (m, 1H); 5.41 (s, 2H); 4.1 (m,2H); 3.14 (m, 2H); 2.73 (s, 3H); 2.23 (m, 1H); 1.65 (m, 1H); 1.56 (m,1H); 1.16 (m, 3H).

[0353] Synthesis of Compound 83 and 84

[0354] Compounds 83 and 84 were synthesized from 29 following proceduressimilar to transformation of 29 to 80 and 81 (Method 28).

[0355] Synthesis of Compound 85

[0356] Compound 85 was synthesized from 84 following a procedure similarto transformation from 29 to 30 (Method 9) and from 30 to 33 (Method10).

[0357]¹H NMR (CD₃OD): δ 8.41 (m, 1 H); 8.06-8.22 (m, 3H); 7.94 (m, 1H);7.54 (m, 1H); 7.26 (m, 2H); 5.88 (s, 2H); 4.07 (m, 2H); 2.98-3.25 (m,2H); 2.87 (s, 3H); 2.23 (m, 1H); 1.54 (m, 2H); 1.16 (m, 3H).

[0358] Synthesis of Compound 86

[0359] Compound 86 was synthesized following a procedure similar to thetransformation of 62 to 63a (Method 20).

[0360] Synthesis of Compound 87

[0361] A mixture of resin 86 (0.070 g, ˜0.7 mmol/g) and 1-methylpiperazine (0.5 mL) in toluene (1 mL) was agitated at 80° C. for 68hours. The liquid was drained, and the resin was washed with analternating cycle of CH₂Cl₂ (3×), THF (3×), and MeOH (3×). The resin wasdried under vacuum for 10 minutes. The cartridge was charged with 75%TFA/CH₂Cl₂ and agitated at room temperature for 24 hours. The liquid wascollected, and the resulting black resin was washed with CH₂Cl₂ (3×).The solvent was removed, and the residue was purified by reverse phaseHPLC to provide 87.

[0362]¹H NMR (CD₃OD): δ 7.92-7.90 (m, 1H), 7.75-7.73 (m, 1H), 7.63-7.58(m, 1H), 7.37-7.34 (m, 2H), 7.21-7.19 (m, 2H), 6.99-6.97 (m, 2H), 5.48(s, 2H), 4.09-3.98 (m, 6H), 3.29-3.27 (m, 4H), 3.22-3.18 (m, 1H),3.04-3.00 (m, 1H), 2.86 (s, 3H), 2.28-2.23 (m, 1H), 1.55-1.53 (m, 2H),1.17-1.13 (m, 3H).

[0363] Synthesis of Compound 88

[0364] Compound 88 was prepared from 49 following a procedure similar tothe transformation of 2 to 3 (Method 1).

[0365] Synthesis of Compound 89

[0366] A mixture of 88 and pyrrolidine in DME was irradiated in amicrowave (100° C. for 25 minutes). The mixture was concentrated andpurified by reverse phase HPLC to provide the product 89.

[0367] Synthesis of Compound 90

[0368] Compound 90 was prepared from 89 following a procedure similar tothe transformation from 55 to 56 (Method 17).

[0369]¹H NMR (CD₃OD): δ 8.06-8.03 (m, 1H), 7.95-7.93 (m, 1H), 7.83-7.80(m, 1H), 7.57-7.53 (m, 1H), 7.40-7.38 (m, 1H), 7.23-7.19 (m, 1H),7.09-7.02 (m, 2H), 5.63 (s, 2H), 3.82-3.78 (m, 4H), 3.63 (s, 3H),3.22-3.18 (m, 1H), 3.06-3.02 (m, 1H), 2.31-2.05 (m, 5H), 1.58-1.52 (m,2H).

[0370] Synthesis of Compound 93

[0371] To a 250 mL round bottom flask containing aniline (1.8 mL, 20mmol) was added concentrated HCl (5 mL) followed by chloranil (4.9 g 20mmol) and n-BuOH. The mixture was heated to reflux and stirredvigorously at which time a solution of pentenal (2.4 mL, 24.5 mmol) inn-BuOH (2 mL) was added slowly over a 45 minute period. After theaddition was complete, the mixture was refluxed for another 20 minutesand then cooled to room temperature. The mixture was diluted with ethylacetate, and the organic layer was separated which was discarded. Theaqueous phase was basicified with a saturated solution of Na₂CO₃ andextracted with ethyl acetate (3×). The collected organic layers weredried (Na₂SO₄), filtered, and concentrated. The brown oil was purifiedby flash chromatography to give compound 93.

[0372] Synthesis of Compound 94

[0373] To a solution of 93 (0.927, 5.9 mmol) in MeOH (12 mL) and H₂O (6ml) was added concentrated H₂SO₄ (0.300 mL) followed by iron powder(0.100 g, 1.8 mmol). The reaction was evacuated and flash with nitrogen(3×) and then cooled to 0° C. Hydroxylamine-O-sulfonic acid (2.0 g, 17.7mmol) was added and the resulting mixture was stirred at 0° C. for 15minutes and at room temperature for 5 hours. The mixture was basicifiedwith a saturated Na₂CO₃ solution and diluted with CH₂Cl₂. The organiclayer was removed, and the aqueous layer was extracted with CH₂Cl₂ (4×).The combined organic layers were dried (Na₂SO₄), filtered, andconcentrated. The residue was purified by flash chromatography to givecompound 94.

[0374] Synthesis of Compound 95

[0375] Compound 95 was synthesized from 94 following a procedure similarto the transformation of 53 to 54 (Method 16).

[0376] Synthesis of Compound 96

[0377] Compound 96 was synthesized from 95 following a procedure similarto the transformation of 47 to 57 (Method 18).

[0378]¹H NMR (CD₃OD): δ 8.10 (m, 1H), 8.03 (m, 1H), 7.79 (m, 1H), 7.67(s, 1H), 7.63 (m, 1H), 7.12 (m, 1H), 7.05 (m, 1H), 6.98 (m, 1H); 5.63(s, 2H), 3.57 (s, 3H), 3.0-3.2 (m, 2H), 3.0 (m, 2H), 2.26 (m, 1H); 1.52(m, 2H); 1.35 (m, 3H).

[0379] Synthesis of Compound 97

[0380] Compound 97 was synthesized from 29a following procedures similarto the transformation of 43 to 47 (Method 13) and 47 to 57(Method 18).

[0381] Synthesis of Compound 98

[0382] Compound 98 was synthesized from 97 following procedures similarto the transformation of 50 to 56 (Method 17).

[0383]¹H NMR (CD₃OD): δ 9.48 (s, 1H); 9.07 (m, 1H); 8.80 (m, 1H); 8.30(s, 1H), 8.21 (m, 2H), 7.98 (m, 1H), 7.87 (s, 1H), 7.73 (m, 1H), 7.22(m, 2H), 7.04 (m, 2H), 5.70 (s, 2H), 4.04 (m, 2H), 2.95-3.22 (m, 2H),2.24 (m, 1H), 1.51 (m, 2H); 1.12 (m, 3H).

[0384] Synthesis of Compound 99

[0385] Compound 99 was synthesized from 30 following procedures similarto the transformation from 30 to 32 (Method 10).

[0386] Synthesis of Compound 100

[0387] Compound 99 (0.07 g, 0.17 mmol), (L)-serine methyl ester (26 mg,0.17 mmol), and N-methyl morpholine (51 mg, 0.5 mmol) were dissolved inDMF. After addition of EDCl (48 mg, 0.25 mmol), the reaction mixture wasstirred overnight at rt. The reaction mixture was diluted with EtOAc,washed with water, and concentrated. The crude product was purified viasilica gel chromatography using a 2:1 EtOAc:Hexanes mobile phase to give58 mg of compound 100.

[0388] Synthesis of Compound 101

[0389] Compound 101 was synthesized from 100 following a proceduresimilar to the transformation of 50a to compound 51b (Method 15).

[0390]¹H NMR (300 MHz, CD₃OD): δ 8.08 (m, 1H), 7.98 (m, 1H), 7.74 (m,1H), 7.57 (m, 2H), 7.18 (m, 2H), 6.95 (m, 2H), 5.54 (s, 2H), 4.4 (m,1H), 4.04 (m, 2H); 3.72 (m, 2H); 2.94-3.22 (m, 2H), 2.70 (s, 3H); 2.51(m, 1H), 1.52 (m, 2H), 1.14 (m, 3H).

[0391] Synthesis of Compound 103

[0392] Compound 103 was synthesized from compound 102 followingprocedures similar to the transformation from 16 to 19 (Method 5).

[0393] Synthesis of Compound 104

[0394] Compound 104 was synthesized from 103 following proceduressimilar to the transformation from 6 to 10 (Method 2).

[0395]¹H NMR-(CD₃CN): δ 7.41-7.61 (m, 5H), 7.25 (m, 1H), 6.92 (m, 3H),5.17 (s, 2H), 3.67 (s, 3H), 3.08-3.33 (m, 2H), 2.35 (m, 1H), 1.64 (m,1H); 1.56 (m, 1H).

[0396] Synthesis of Compound 107

[0397] To a solution of methyl 2-(bromomethyl)acrylate 105 (2.0 mL, 16.6mmol) and m-nitrophenylboronic acid 106 (3.0 g, 17.9 mmol) in toluene(150 mL) was added Pd(dppf)Cl₂.CHCl₃ (0.978 g, 1.34 mmol) and aqueous 3NK₂CO₃ (16 mL). The mixture was heated to reflux and stirred for 1 hour.The solution was cooled to room temperature and diluted with 1N NaOH(150 mL) and EtOAc (150 mL). The aqueous layer was removed, and theorganic phase was washed with 1N NaOH (2×). The organic phase was dried(Na₂CO₃), filtered, and concentrated. The mixture was purified by flashchromatography to furnish compound 107 (0.880 g).

[0398] Synthesis of Compound 108

[0399] Compound 108 was synthesized from 107 following a proceduresimilar to the transformation of 4 to 5 (Method 1).

[0400] Synthesis of Compound 109

[0401] A mixture of Compound 108 (0.450 g, 1.34 mmol) and 10% Pd/C(0.120 g) in MeOH was stirred at room temperature under an atmosphere ofH₂ for 1.5 hours. The mixture was filtered through a pad of silica andconcentrated to give the aniline, which was used for next step withoutpurification. To a solution of crude aniline (prepared above) andpyridine (0.230 mL, 2.84 mmol) in CH₂Cl₂ (20 mL) was addedp-methoxyphenyl sulfonylchloride (0.284 g, 1.37 mmol). The mixture wasstirred for 2 hours and then concentrated. The oil was purified by flashchromatography to provide compound 109(0.541 g) as foam.

[0402] Synthesis of Compound 111

[0403] To a solution of Compound 109 (0.147 g, 0.31 mmol) and K₂CO₃(0.135 g, 0.98 mmol) in DMF (0.700 mL) was added Mel (0.021 mL, 0.34mmol). The reaction was stirred for 1.5 hours under nitrogen, quenchedwith H₂O, and diluted with EtOAc. The organic layer was separated, andthe aqueous phase was extracted with EtOAc (3×). The combined organicswere washed with H₂O (2×), dried (Na₂SO₄), filtered, and concentrated toprovide compound 111 (0.141 mg).

[0404] Synthesis of Compound 112

[0405] Compound 112 was synthesized from 111 following proceduressimilar to the transformation of 7 to 10 (Method 2).

[0406]¹H NMR (CDCl₃): δ 7.50 (m, 2H), 7.14-7.17 (m, 3H), 6.92 (m, 2H),6.57 (m, 1H), 3.86 (s, 3H), 3.73 (m, 1H), 3.70 (s, 3H), 3.10 (s, 3H),3.01-2.97 (m, 1H), 1.71-1.59 (m, 2H), 1.27-1.24 (m, 1H).

[0407] Synthesis of Compound 110

[0408] Compound 110 was synthesized from 109 following proceduressimilar to the transformation of 7 to 10 (Method 2).

[0409]¹H NMR (CDCl₃) of 110: δ 7.67 (m, 2H), 7.09-6.97 (m, 3H), 6.88 (m,2H), 6.72 (m, 1H), 3.81 (s, 3H), 3.62 (s, 3H), 3.34 (m, 1H), 3.02 (m,1H), 2.41-2.37 (m, 1H), 1.65-1.62 (m, 1H), 1.55-1.52 (m, 1H).

[0410] Synthesis of Compound 113

[0411] Compound 113 was synthesized from 114 following proceduressimilar to the transformation of 107 to 110 (Method 36).

[0412]¹H NMR (CD₃OD): δ 7.65-7.63 (m, 2H), 7.10-7.08 (m, 2H), 6.97-6.94(m, 4H), 4.03-3.98 (m, 2H), 3.82 (s, 3H), 3.16-3.12 (m, 1H), 3.02-2.98(m, 1H), 2.27-2.24 (m, 1H), 1.53-1.50 (m, 2H), 1.08-1.05 (m, 3H).

[0413] Synthesis of Compound 115

[0414] Compound 115 was synthesized from 114 following proceduressimilar to the transformation of 107 to 112 (Method 36).

[0415]¹H NMR (CD₃OD): δ 7.45-7.42 (m, 2H), 7.20-7.18 (m, 2H), 7.02-6.96(m, 4H), 4.09-4.04 (m, 2H), 3.87 (s, 3H), 3.23-3.20 (m, 1H), 3.13-3.10(m, 1H), 3.12 (s, 3H), 2.32-2.28 (m, 1H), 1.57-1.54 (m, 2H), 1.14 (m,3H).

[0416] Synthesis of Compound 116

[0417] To a TFA solution of 219 mg (1.09 mmol) compound 29 was added 2eq of Selectfluor and the solution was stirred overnight. Afterevaporation of solvent, the residue was chromatographed on a C-18reverse phase column to give 24 mg of compound 116.

[0418] Synthesis of Compound 117

[0419] Compound 117 was synthesized from 116 following proceduressimilar to the transformation of 29 to 30 (Method 9) and then 30 to 33(Method 10).

[0420]¹H NMR (CD₃OD): δ 8.19 (m, 1H), 8.05 (m, 1H), 7.87 (m, 1H), 7.75(s, 1H); 7.70 (m, 1H); 7.15 (m, 1H); 7.06 (m, 1H); 7.00 (m, 1H); 5.70(s, 2H), 4.06 (m, 2H), 3.02-3.21 (m, 2H), 2.79 (s, 3H), 2.26 (m, 1H),1.53 (m, 2H), 1.14 (m, 3H)

[0421] Synthesis of Compounds 119 and 120

[0422] To a solution of 118 (0.63 g, 3.30 mmol) in 8 mL of anhyd. THF at−78° C. was added 1.8 mL of 2 M LDA in THF, and the reaction mixture wasstirred at −78° C. for 1 h. A solution of 4-benzyloxybenzylbromide (0.94g, 3.39 mmol) in 2 mL of anhyd. THF was added via addition funnel. Thereaction mixture was stirred and allowed to warm to 23° C. overnight.The reaction was quenched with 5 mL of saturated NH₄Cl and extract with20 mL of diethyl ether. The organic solution was washed with 5 mL ofbrine, dried (MgSO₄), filtered, and concentrated in vacuo. Purificationby flash silica gel chromatography gave 0.11 g (9%) of compound 119 and0.40 g (31%) of compound 120.

[0423] Synthesis of Compound 121

[0424] Compound 121 was synthesized from 119 following proceduressimilar to the transformations of 18 to 19 (Method 5) and 30 to 33(Method 10).

[0425]¹H NMR (DMSO): δ 10.74 (s, 1H), 8.79 (s, 1H), 8.07(m, 1H), 7.95(m, 1H), 7.59-7.74 (m, 1H), 7.53-7.58 (m, 1H), 7.51 (s, 1H), 7.05 (m,2H), 6.96 (m, 2H), 5.53 (s, 2H), 3.63 (m, 1H), 3.46 (s, 3H), 3.05 (m,1H), 2.63 (s,3H), 1.97 (s, 1H), 1.34 (s, 3H), 1.03 (s, 3H).

[0426] Synthesis of Compounds 122 and 123

[0427] Compound 122 was prepared from isatin according to the proceduredescribed by H. W. Tsao, U.S. Pat. No. 4,267,33; May 12, 1981. The acidwas reduced to the alcohol using cyanuric fluoride and sodiumborohydride according to the procedure in G. Kokotos and C. Noula J.Org. Chem. 1996, 61, 6994-6996.

[0428] Compound 124 was prepared according to the procedure in A. G.Taveras et al US Patent 2002 U.S. Pat. No. 6,327,47.

[0429] Compound 125 was prepared according to a procedure similar to theone described by F. J. Lotspeich J. Org. Chem. 1967, 32, 1274-1277.

[0430] Synthesis of Compound 128

[0431] Compound 128 was synthesized from 127 following a proceduresimilar to the transformation of 19a to 23.

[0432] Synthesis of Compound 129

[0433] A solution of compound 128 (4.0 g, 11.73 mmol) in anhyd CH₂Cl₂(60 mL) was cooled to 0° C. with a ice-water bath before PBr₃ (1.1 mL,11.73 mmol, in 5 mL anhyd CH₂Cl₂) was added. The solution was stirred at0° C. for 4 hours and at rt for 12 hours before it was poured into acold saturated aq NaHCO₃ (250 mL) with stirring. The aq layer wasextracted with CH₂Cl₂ (4×). The combined organic layers were washed withbrine (100 mL), dried over anhyd Na₂SO₄, and concentrated. The residuewas dried under vacuum for 4 hours to give compound 129(4.3 g, 91%).

[0434] Synthesis of Compound 131 and 132

[0435] To a 100 mL round bottom flask was added diisopropyl amine (1.0mL, 7.16 mmol) and anhyd THF (10 mL). The solution was cooled to −40° C.before n-BuLi (1.45 M, 4.5 mL, 6.52 mmol) was added dropwise via asyringe. The solution was gradually warmed up to −20° C. in 20 minutesbefore it was cooled to 31 78° C. The above solution was added to asolution of cis-dimethyl 1,2-cyclobutane diester 130 (1.02 g, 5.92 mmol)in anhyd THF (10 mL) at −78° C. via a cannula. The solution was stirredat −78° C. for an hour followed by addition of compound 129 (1.9 g, 4.74mmol) in anhyd THF (5 mL). The solution was stirred at −78° C. for 4 h,and allowed to gradually warmed up to room temperature overnight beforesat aq NH₄Cl (50 mL) was added. The aq layer was extracted withEtOAc(3×) and the combined organic layers were dried over anhyd Na₂SO₄,and concentrated. The residue was chromatographed to give compounds 131and 132 (110 mg).

[0436] Synthesis of Compound 133

[0437] Compound 133 was synthesized from 132 following a proceduresimilar to the transformation of 50a to 51b(Method 15).

[0438]¹H-NMR (CD₃OD, 300 MHz): δ 8.16 (m, 2H), 8.08 (m, 3H), 7.81 (m,1H), 7.65 (m, 1H), 7.58-7.50 (m, 3H), 7.06 (m, 2H), 7.01 (m, 2H), 5.66(s, 2H), 3.63 (s, 3H), 3.18 (m, 1H), 3.11 (m, 1H), 3.05 (m, 1H), 2.37(m, 2H), 2.13 (m, 1H), 1.94 (m, 1H).

[0439] Synthesis of Compound 135

[0440] Compound 135 was synthesized from 134 following a proceduresimilar to the transformation of 51 to 53(Method 16).

[0441] Synthesis of Compound 136

[0442] Compound 135 (1.45 g/10.1 mmol) was dissolved in 20 mL of tolueneand morpholine (8.6 mL) was added. The reaction mixture was stirredunder N₂ at 110 C over the weekend then concentrated to give 8.2 g of ayellow oil which was purified to give compound 136.

[0443] Synthesis of Compound 137

[0444] Compound 137 was synthesized from 136 following a proceduresimilar to the transformation of 53 to 54(Method 16).

[0445] Table 1 below provides preferred compounds of the presentinvention and associated LCMS and/or HNMR data. TABLE 1 Rt M + 1Structures (min) (Obs) 1H NMR Method A

4.56 342 1H NMR (CD3CN): d 7.6-7.4 (m, 5H); 7.3 (m, 1H); 6.95 (m, 3H);5.2 (m, 2H); 3.7 (s, 3H); 2.6 (m, 1H); 2.05 (m, 1H); 1.85 (m, 1H). 2 B

2.91 266 1H NMR (CD3CN): d 7.35 (m, 1H); 6.95 (m, 3H); 3.9 (s, 3H); 3.71(s, 3H); 2.6 (m, 1H); 2.05 (m, 1H); 1.85 (m, 1H). 2 C

307 2a D

392 2AB E

3.46 327 1H NMR (CD3CN): d 7.6-7.35 (m, 5H); 7.4 (m, 1H); 7.05 (m, 3H);6.4 (br s, 1H); 5.85 (br s, 1H); 5.2 (m, 2H); 2.6 (m, 1H); 1.9 (m, 1H);1.75 (m, 1H). 3 F

2.05 251 1H NMR (CD3CN): d 7.4 (m, 1H); 7.02 (m, 3H); 6.1 (br s, 1H);5.75 (br s, 1H); 3.9 (s, 3H); 2.6 (m, 1H), 1.9 (m, 1H); 1.75 (m, 1H).2ABC; 3 G

383 4A′; 2BC; 3AB H

5.56 397 4A′ I

4.31 384 4A′; 3A J

412 1H NMR (CDCl3): d 7.3-7.5(m, 5H); 7.20 (m, 2H); 6.9 (m, 2H); 5.0 (s,2H); 4.1(m, 2H); 3.15(m, 0.3H); 2.5 (m, 0.5 H); 2.05 (m, 1H); 1.7-1.9(m, 1.2 H); 1.3 (br. s, 3 H) 1.2 (m, 3H); 1.1 (br. s, 6 H) 4A′ K

4.66 341 4A′; 2B L

411 5AB M

4.26 395 6 N

3.86 355 6 O

2.45 496 7A; 6 P

1.95 497 7A; 6 Q

3.64 492 7A; 6 R

3.98 520 7A; 6 S

2.25 448 7A; 6 T

3.88 462 7A; 6 U

3.68 448 7A; 6 V

2 420 7A; 6 W

3.84 462 7A; 6 X

2.6 510 7A; 6 Y

1.95 497 7A; 6 Z

3.84 462 7A; 6 AA

3.95 474 7A; 6 AB

4.11 510 7A; 6 AC

4.32 524 7A; 6 AD

2.5 488 7A; 6 AE

2.35 489 7A; 6 AF

4.08 482 7A; 6 AG

2.55 510 7A; 6 AH

4.41 431 1H NMR (CD3CN/D2O, 2:1): d 7.29-7.44 (m, 6H), 7.14-7.07 (m,4H), 6.84 6.81 (m, 4H), 5.03 (s, 2H), 4.22-4.13 (m, 2H), 3.12-2.93 (m,2H), 2.07-2.03 (m, 1H), 1.49-1.46 (m, 1H), 1.40 1.38 (m, 1H). 6 AI

3.91 462 7A; 6 AJ

3.66 424 6 AK

3.61 432 6 AL

3.61 432 6 AM

4.61 445 6 AN

4.41 461 6 AO

4.01 369 6 AP

4.46 449 6 AQ

4.56 423 6 AR

4.56 445 6 AS

4.41 447 6 AT

4.56 445 6 AU

3.78 518 7A; 6 AV

4.18 568 7A; 6 AW

3.68 460 7A; 6 AX

3.48 446 7A; 6 AY

3.21 489 7A; 6 AZ

341 5AB; 2B BA

492 34 BB

554 34 BC

4.01 406 7AB BD

3.76 421 7 BE

3.76 421 7 BF

3.96 318 1H NMR (CD3CN): d 7.15 (m, 2H), 6.84 (m, 2H), 4.64-4.62 (m,2H), 3.58 (s, 3H), 3.15-2.94 (m, 2H), 2.22-2.18 (m, 1H), 1.83-1.81 (m,3H), 1.52-1.46 (m, 2H). 7 BG

4.71 356 1H NMR (CDCl3): d 7.42-7.31 (m, 5H), 7.12 (m, 2H), 6.86 (m,2H), 5.01 (s, 2H), 3.63 (s, 3H), 3.20-3.09 (m, 2H), 2.17 (m, 1H),1.64-1.58 (m, 2H) 7 BH

3.96 406 7AB BI

5.05 449 8AB BJ

2.65 449 8AB BK

2.8 463 8AB BL

2.15 434 1H NMR (CD3OD): d 8.42-8.40 (m, 1H), 8.19-8.09 (m, 3H),7.96-7.92 (m, 1H), 7.14-7.05 (m, 4H), 5.82 (s, 2H), 3.07 (s, 2H), 3.01(s, 3H), 2.99 (s, 3H), 2.82 (s, 3H), 1.91-1.88 (m, 1H), 1.54-1.51 (m,1H), 1.37-1.34 (m, 1H). 8AC BM

3.58 469 10AB; 7C; 8A; 2D BN

3.36 407 8A; 2D BO

488 15A; 10BD BP

531 15A; 10BD BQ

551 1H NMR (CD3OD): δ 8.02-8.18 (m, 5H); 7.72-7.82(m, 2H); 7.42-7.68(m,4H); 7.04-7.18(m, 2H); 6.96-7.04(m, 2H); 5.59(s, 2H); 3.82-4.02(m, 2H);3.44-3.70(m, 2H); 2.96-3.20 (m, 4H); 1.82-1.96 (m, 1H); 1.50-1.62(m,1H); 1.28-1.40(m, 1H). 10ABD BR

565 1H NMR (CD3OD): δ 8.0-8.18 (m, 5H); 7.72-7.80 (m, 1H); 7.56-7.62(m,1H); 7.42-7.56(m, 3H); 7.14-7.26 (m, 2H); 6.98-7.08 (m, 2H); 5.55 (s,2H); 3.08-3.26 (m, 2H); 2.76-2.92 (m, 4H); 2.24-2.42(m, 2H);2.04-2.16(m, 1H); 1.40-1.56 (m, 2H); 1.16-1.40(m, 3H); 0.76-0.96 (m,2H). 10ABD BS

4.88 497 1H NMR (CD3OD): δ 8.54-8.51 (m, 2H), 8.44-8.42 (m, 1H),8.24-8.20(m, 1H), 8.13-8.11 (m, 2H), 8.05-8.01 (m, 1H), 7.83-7.75 (m,3H), 7.28 7.25 (m, 2H), 7.13-7.10 (m, 2H), 5.95 (s, 2H), 4.08-4.02 (m,2H), 3.24-3.20 (m, 1H), 3.04-3.00 (m, 1H), 2.28-2.24 (m, 1H), 1.56-1.54(m, 2H), 1.16 1.12 (m, 3H). 10ABC BT

5.22 420 10ABC BU

5.15 420 10ABC BV

4.71 449 1H NMR(400 MHz, CD3OD): d 8.14-8.02 (m, 2H); 7.79-7.74 (m, 1H);7.62-7.58 (m, 2H); 7.22-7.20 (m, 2H); 7.00-6.98 (m, 2H); 5.57 (s, 2H);4.08-4.03 (m, 2H), 3.22-3.18 (m, 1H), 3.03-2.96 (m, 3H); 2.27-2.24 (m,1H); 1.55-1.53 (m, 2H); 1.39-1.34 (m, 3H), 1.16 (m, 3H). 10ABC BW

3.11 406 8AC BX

3.61 421 1H NMR (CD3CN): d 8.38 (m, 1H), 8.28 (m, 1H), 8.06-8.02 (m,2H), 7.90 7.86 (m, 1H), 7.23 (d, 2H), 7.04 (d, 2H), 5.72 (s, 2H), 3.59(s, 3H), 3.16-2.99 (m, 2H), 2.96 (s, 3H), 2.25-2.21 (m, 1H), 1.54-1.47(m, 2H) 7 BY

498 1H NMR(400 MHz, CD3OD): d 9.48 (s, 1H); 9.07 (m, 1H); 8.80 (m, 1H);8.30 (s, 1H), 8.21 (m, 2H), 7.98 (m, 1H), 7.87 (s, 1H), 7.73 (m, 1H),7.22 (m, 2H), 7.04 (m, 2H), 5.70 (s, 2H), 4.04 (m, 2H), 2.95-3.22 (m,2H), 2.24 (m, 1H), 1.51 (m, 2H); 1.12 (m, 3H). 10ABC BZ

3.71 485 10ABD CA

435 1H NMR(300 MHz, CD3OD): δ8.01 (m, 1H), 7.96 (m, 1H), 7.74-7.69 (m,1H), 7.57-7.52 (s, 1H), 7.19 (m, 2H), 6.943 (m, 2H), 5.47 (s, 2H), 4.05(m, 2H), 3.29-3.02 (m, 2H), 2.66 (s, 3H), 2.30-2.20 (m, 1H), 1.60-1.48(m, 2H), 1.10 (m, 3H). 15 CB

507 15 CC

489 15 CD

507 15 CE

474 15A; 10B CF

519 15 CG

518 15 CH

469 15 CI

510 15 CJ

416 15 CK

474 15 CL

573 15 CM

506 15A CN

3.71 453 1HNMR(400 MHz, CD3OD): d 7.97-7.92 (m, 1H), 7.82-7.80 (m, 1H),7.67 7.64 (m, 1H), 7.39-7.34 (m, 2H), 7.21 7.02 (m, 3H), 5.57 (s, 2H),3.31-3.29 (m, ) 2.19-2.14 (m, 1H), 1.55-1.51 (m, 1H), 1.46-1.43 (m, 1H),14, 31 CO

3.61 438 1HNMR(400 MHz, CD3OD): d 8.16-8.04 (m, 2H), 7.86-7.82 (m, 1H),7.74 (s, 1H), 7.69-7.65 (m, 1H), 7.18-7.00 (m, 3H), 5.65 (s, 2H),3.26-3.13 (m, 2H), 3.07-3.02 (m, 2H), 2.18-2.14 (m, 1H), 1.56-1.53 (m,1H), 1.46-1.37 (m, 4H). 17 CP

4.78 486 1H NMR(400 MHz, CD3OD): d 8.35 (m, 2H); 8.3 (m, 1H); 8.15 (m,2H); 8.05 (m, 1H); 7.85 (m, 1H); 7.65 (m. 3H); 7.25 (m,, 1H); 7.0-7.15(m, 2H); 5.95 (s, 2H); 3.1-3.3 (m, 2H); 2.15 (m, 1H); 1.55 (m, 1H); 1.45(m, 1H). 17 CQ

3.84 487 1H NMR(400 MHz, CD3OD): d 9.4 (br. s, 1H); 8.7-8.9 (m, 2H);8.15-8.25(m, 3H); 8.1 (s, 1H); 7.78-7.85(m, 2H); 7.6-7.7(m, 2H);7.0-7.25(m, 3H); 5.6(s, 2H); 3.1-3.25(m, 2H); 2.15(m, 2H); 1.5(m, 1H);1.45(m, 1H). 17 CR

3.64 452 1H NMR(400 MHz, CD3OD): d 8.15(m, 1H); 8.05 (m, 1H); 7.75 (m,1H); 7.6(m, 2H); 6.95-7.2 (m, 3H); 5.62(s, 2H); 3.1-3.15(m, 2H); 2.95(m, 2H); 2.15 (m, 1H); 1.8 (m, 2H); 1.55 (m, 1H); 1.45 (m, 1H); 1.0 (m,3H). 17 CS

487 17 CT

2.84 424 1H NMR(400 MHz, CD3OD): d 8.41(m, 1H); 8.1-8.2 (m, 3H); 7.95(m, 1H); 7.25 (m, 1H); 7.05-7.15 (m, 2H); 5.95 (s, 2H); 3.1-3.3 (m, 2H);3.02 (s, 3H); 2.18 (m, 1H); 1.55 (m, 1H); 1.45 (m, 1H). 12; 10ABD CU

4.01 450 1H NMR (CD3OD): δ 8.08 (m, 1H); 7.95 (m, 1H); 7.75 (m, 1H);7.55 (m, 1H); 7.4 (s, 1H); 7.0-7.2 (m, 3H); 5.6(s, 2H); 3.1-3.3 (m, 2H);2.3 (m, 1H); 2.15(m, 1H); 1.55(m, 1H); 1.45(m, 1H); 1.05-1.2 (m, 4H). 17CV

3.04 424 17 CW

4.48 520 17 CX

4.01 570 17 CY

520 NMR 17 CZ

515 14B; 17 DA

3.28 469 17 DB

4.41 453 18 DC

3.59 439 18 DD

3.74 465 18 DE

4.55 453 1H NMR (CD3OD): δ 8.19(m, 1H), 8.05 (m, 1H), 7.87 (m, 1H), 7.75(s, 1H); 7.70 (m, 1H); 7.15 (m, 1H); 7.06 (m, 1H); 7.00 (m, 1H); 5.70(s, 2H), 4.06 (m, 2H); 3.02-3.21 (m, 2H), 2.79 (s, 3H), 2.26 (m, 1H),1.53 (m, 2H), 1.14 (m, 3H) 18 DF

4.81 482 20 DG

4.96 424 20 DH

4.91 424 20 DI

4.86 424 20 DJ

4.68 423 20AB; 6C DK

4.61 390 20 DL

4.71 435 20 DM

4.35 427 20 DN

3.16 357 20 DO

4.26 4.66 390 20 DP

4.91 438 20 DQ

4.08 437 20 DR

4.21 332 20 DS

3.88 421 20 DT

4.58 453 20 DU

5.02 506 20 DV

3.44 385 20 DW

4.05 412 20 DX

4.31 406 20 DY

3.21 374 20 DZ

4.91 362 20 EA

3.78 450 20 EB

4.11 484 20 EC

4.36 406 20 ED

4.86 420 20 EE

420 20 EF

460 20 EG

420 20 EH

384 20 EI

434 20 EJ

396 20 EK

410 20 EL

434 20 EM

420 20 EN

5.15 406 21 EO

4.78 415 21 EP

4.91 424 21 EQ

4.55 400 21 ER

4.51 381 21 ES

4.78 370 21 ET

4.65 401 21 EU

5.18 424 21 EV

4.61 386 21 EW

4.58 386 21 EX

4.65 401 21 EY

4.88 390 21 EZ

4.61 356 21 FA

4.95 406 21 FB

4.85 390 21 FC

4.78 370 21 FD

4.18 434 21 FE

4.98 384 21 FF

432 21 FG

4.28 388 23 FH

3.38 388 23 FI

3.48 460 24 FJ

3.95 446 24 FK

4.01 431 25 FL

3.78 430 26 FM

393 27 FN

3.75 440 28A; 9C; 10ABD FO

4.61 469 28 FP

503 28 FQ

3.78 485 29A; 9C; 10ABD FR

4.28 514 29 FS

593 29 FT

5.18 526 30 FU

4.05 479 1HNMR(400 MHz, CD3OD): d 8.05-8.03 (m, 1H), 7.95-7.93 (m 1H),7.84-7.80 (m, 1H), 7.57-7.53 (m, 1H), 7.39 (m, 1H), 7.25-7.20 (m, 1H),7.11-7.04 (m, 2H), 5.63 (m, 2H), 3.81-3.78 (m, 4H), 3.27-3.14 (m, 2H),2.21-2.17 (m, 5H), 1.57-1.53 (m, 1H), 1.45 1.43 (m, 1H). 14; 31 FV

4.18 493 1HNMR(400 MHz, CD3OD): d 8.01-7.99 (m, 1H), 7.92-7.90 (m, 1H),7.79 7.75 (m, 1H), 7.52-7.48 (m, 1H), 7.34 (s, 1H), 7.22-7.18 (m, 1H),7.11-7.03 (m, 2H), 5.63 (m, 2H), 4.51-4.46 (m, 1H), 3.91-3.88 (m, 1H),3.71-3.64 (m, 1H), 3.27-3.12 (m, 2H), 2.30-2.13 (m, 4H), 1.95-1.93 (m,1H), 1.55 1.53 (m, 1H), 1.45-1.43 (m, 1H), 1.33 1.31 (m, 3H). 14; 31 FW

3.64 495 1HNMR(400 MHz, CD3OD): d 7.90-7.88 (m, 1H), 7.73-7.71 (m, 1H),7.60 7.56 (m, 1H), 7.34-7.30 (m, 2H), 7.16 6.99 (m, 3H), 5.51 (s, 2H),3.82-3.80 (m, 4H), 3.71-3.69 (m, 4H), 3.25-3.12 (m, 2H), 2.17-2.14 (m,1H), 1.55 1.52 (m, 1H), 1.47-1.43 (m, 1H). 14; 31 FX

3.31 508 1H NMR (CD3OD): δ 8.08-8.06 (m, 2H), 7.85-7.81 (m, 1H),7.63-7.57 (m, 2H), 7.23-7.18 (m, 1H), 7.10-7.03 (m, 2H), 5.63 (s, 2H),4.28-4.14 (m, 4H), 3.58-3.50 (m, 4H), 3.27-3.14 (m, 2H), 3.00 (s, 3H),2.25-2.18 (m, 1H), 1.56-1.53 (m, 1H), 1.45-1.42 (m, 1H). 14; 31 FY

4.45 494 31 FZ

4.48 510 31 GA

3.78 523 31 GB

4.01 454 31 GC

3.58 509 31 GD

4.05 519 30 GE

522 34 GF

506 34 GG

532 34 GH

506 34 GI

548 34 GJ

534 34 GK

532 34 GL

4.76 356 1H NMR (CD3CN): d 7.6-7.4 (m, 5H); 7.3 (m, 1H); 6.95 (m, 3H);5.2 (s, 2H); 3.7 (s, 3H); 3.3-3.1 (m, 2H); 2.4 (m, 1H); 1.65-1.55 (m,2H). 35 GM

327 35A; 3A; 2B GN

341 35A; 2B GO

6.06 397 35A GP

355 35A; 3A; 2B; 9C GQ

3.91 325 35A; 3A; 2B; 8C GR

3.86 435 1H NMR (CDCl3): d 7.67 (m, 2H), 7.09-6.97 (m, 3H), 6.88 (m,2H), 6.72 (m, 1H), 3.81 (s, 3H), 3.62 (s, 3H), 3.34 (m, 1H), 3.02 (m,1H), 2.41-2.37 (m, 1H), 1.65-1.62 (m, 1H), 1.55-1.52 (m, 1H) 36ABC E GS

4.11 449 1H NMR (CDCl3): d 7.50 (m, 2H), 7.14-7.17 (m, 3H), 6.92 (m,2H), 6.57 (m, 1H), 3.86 (s, 3H), 3.73 (m, 1H), 3.70 (s, 3H), 3.10 (s,3H), 3.01-2.97 (m, 1H), 1.71-1.59 (m, 2H), 1.27-1.24 (m, 1H). 36ABC DFGT

4.06 449 1H NMR (CD3OD): d 7.65-7.63 (m, 2H), 7.10-7.08 (m, 2H),6.97-6.94 (m, 4H), 4.00 (q, 2H), 3.82 (s, 3H), 3.16-2.98 (m, 2H),2.27-2.24 (m, 1H), 1.53-1.49 (m, 2H), 1.06 (m, 3H) 37A GU

4.36 463 1H NMR (CD3OD): d 7.45-7.42 (m, 2H), 7.20-7.18 (m, 2H),7.02-6.96 (m, 4H), 4.06 (q, 2H), 3.87 (s, 3H), 3.23-3.09 (m, 2H), 3.12(s, 3H), 2.32-2.28 (m, 1H), 1.57-1.54 (m, 2H), 1.14 (m, 3H) 37B GV

4.71 530 38 GW

4.41 515 38 GX

449 1HNMR(300 MHz, DMSO), d 10.74(s, 1H), 8.79(s, 1H), 8.07(m, 1H),7.95(m, 1H), 7.74-7.59(m, 1H), 7.58-7.53(m, 1H), 7.51(s, 1H), 7.05(m,2H), 6.96(m, 2H), 5.53(s, 2H), 3.63(m, 1H), 3.46(s, 3H), 3.05(m, 1H),2.63 (s, 3H), 1.97(s, 1H), 1.34(s, 3H), 1.03(s, 3H) 39 GY

449 1HNMR(300 MHz, DMSO), d 10.42(s, 1H), 8.71(s, 1H), 8.08(m, 1H), 7.95(m, 1), 7.75-7.68 (m, 1H), 7.58-7.48 (m, 2H), 7.10 (m, 2H), 7.02 (m,2H), 5.55 (s, 2H), 3.39 (s, 3H), 3.21 (m, 1H), 2.77 (m, 1H), 2.64 (s,3H), 1.43 (s, 1H), 1.32 (s, 3H), 1.25(s, 3) 39 GZ

434 39A; 10B HA

4.56 410 1; 2B; 20 HB

4.41 468 1; 2B; 20 HC

4.46 421 1; 2B; 20 HD

4.21 387 1; 2B; 20 HE

4.01 4.21 4.41 376 1; 2B; 20 HF

4.66 406 1; 2B; 20 HG

4.66 406 1; 2B; 20 HH

4.21 360 1; 2B; 20 HI

4.16 372 1; 2B; 20 HJ

4.31 386 1; 2B; 20 HK

4.81 424 1; 2B; 20 HL

2.75 2.96 343 1; 2B; 20 HM

4.31 356 1; 2B; 20 HN

4.31 386 1; 2B; 20 HO

4.06 342 1H NMR (CD3CN): d 7.65-7.4 (m, 5H); 7.35 (m, 1H); 7.0 (m, 3H);5.19 (m, 2H); 3.7 (s, 3H); 2.4 (m, 1H); 2.05 (m,); 1.85(m, 1H) 1; 2B; 20HP

4.56 390 1; 2B; 20 HQ

4.86 478 1; 2B; 20 HR

3.91 370 1; 2B; 20 HS

3.96 318 1; 2B; 20 HT

4.61 348 1; 2B; 20 HU

2.91 343 1; 2B; 20 HV

3.76 304 1; 2B; 20 HW

4.11 320 1; 2B; 20 HX

4.31 396 1; 2B; 20 HY

3.76 306 1; 2B; 20 HZ

4.36 376 1; 2B; 20 IA

3.76 4.01 360 1; 2B; 20 IB

4.11 342 1; 2B; 20 IC

4.66 410 1; 2B; 20 ID

3.31 407 1H NMR (CD3CN): d 8.45 (d, 1H); 8.25-8.05 (m, 3H); 7.95 (m,1H); 7.25 (m, 1H); 7.05-6.95 (m, 3H); 5.85 (m, 2H); 3.6 (s. 3H); 3.0 (s,3H); 2.55 (m, 1H); 2.0 (m, 1H); 1.8 (m, 1H). 1; 2B; 20 IE

4.51 410 1; 2B; 20 IF

4.16 387 1; 2B; 20 IG

2.86 392 1H NMR (CD3CN): d 8.45 (m, 1H); 8.25-8.05 (m, 3H); 7.95 (m,1H); 7.25 (m, 1H); 7.05-6.95 (m, 3H); 5.85 (m, 2H); 3.0 (s, 3H); 2.55(m, 1H); 2.0 (m, 1H); 1.8 (m, 1H) 1; 2B; 20 IH

4.18 387 1; 2B; 20AB; 21 II

4.35 378 1; 2B; 20AB; 21 IJ

4.31 356 1; 2B; 20AB; 21 IK

4.11 342 1; 2B; 20AB; 21 IL

3.78 370 1; 2B; 20AB; 21 IM

372 1; 2B; 20AB; 21 IN

4.11 342 1; 2B; 20AB; 21 IO

3.88 358 1; 2B; 21 IP

3.81 353 1; 2B; 20AB; 21 IQ

3.98 373 1; 2B; 20AB; 21 IR

4.01 373 1; 2B; 20AB; 21 IS

3.84 353 1; 2B; 10AB; 21 IT

4.31 342 1; 2B; 20AB; 21 IU

3.91 328 1; 2B; 20AB; 21 IV

4.11, 4.36 392 1; 2B; 20AB; 21 IW

4.95 384 10ABC IX

434 10ABC IY

434 10ABC IZ

3.91 552 1H NMR(400 MHz, CD3OD): d 8.42-8.32 (m, 3H), 8.12-8.06 (m, 3H),7.92 7.88 (m, 1H), 7.72-7.68 (m, 3H), 7.17 7.15 (m, 2H), 7.09-7.07 (m,2H), 5.85 (s, 2H), 3.97-3.88 (m, 1H), 3.52-3.35 (m, 4H), 3.20-3.08 (m,2H), 2.02-1.98 (m, 1H), 1.88-1.82 (m, 1H), 1.77 1 10ABD JA

4.21 565 1H NMR(400 MHz, CD3OD): d 8.35-8.28 (m, 3H), 8.13-8.11 (m, 2H),8.04 7.98 (m, 1H), 7.86-7.81 (m, 1H), 7.67 7.65 (m, 3H), 7.20-7.17 (m,2H), 7.12 7.10 (m, 2H), 5.81 (s, 2H), 3.80-3.43 (m, 5H), 3.14-3.11 (m,1H), 3.03-2.97 (m, 1H), 2.92-2.80 (m, 6H), 2.36 2 10ABD JB

4.21 565 10ABD JC

3.64 490 1H NMR(400 MHz, CD3OD): d 8.46-8.44 (m, 1H), 8.24-8.14 (m, 3H),8.00 7.96 (m, 1H), 7.19-7.06 (m, 4H), 5.85 (s, 2H), 4.38-4.35 (m, 1H),3.65-3.36 (m, 4H), 3.33-3.27 (m,), 3.15-2.99 (m, 2H), 1.96-1.78 (m, 3H),1.54-1.45 (m, 5H). 10ABD JD

3.61 553 1H NMR(400 MHz, CD3OD): d 8.41-8.33 (m, 3H), 8.12-8.10 (m, 3H),7.93 7.90 (m, 1H), 7.71-7.69 (m, 3H), 7.18 7.10 (m, 4H), 5.85 (s, 2H),3.63-3.49 (m, 2H), 3.16-3.09 (m, 7H), 2.92-2.78 (m, 6H), 2.03-2.01 (m,1H), 1.53 1.51 (m, 1H), 1.45-1.42 (m, 1H). 10ABD JE

3.94 633 10ABD JF

3.81 517 10ABD JG

3.48 490 10ABD JH

3.11 409 1H NMR (CD3OD): d 8.44 (m, 1H); 8.16 (m, 3H); 7.97 (m, 1H);7.27 (m, 2H); 7.09 (m, 2H); 5.85 (s, 2H); 3.20 (m, 2H); 3.01 (s, 3H);2.17-2.13 (m, 1H), 1.56-1.52 (m, 1H), 1.48-1.45 (m, 1H) 10ABD JI

3.21 476 10ABD JJ

3.21 476 10ABD JK

3.11 406 10ABD JL

4.01 552 10ABD JM

3.91 439 12; 10AB; 2C; 3A; 3C JN

4.98 514 1H NMR(400 MHz, CD3OD): d 8.4 (d, 1H); 8.39 (s, 1H); 8.35 (m,1H); 8.1 (m, 2H); 8.05 (m, 1H); 7.9 (m, 2H); 7.7 (m, 2H); 7.22 (m. 1H);6.9-7.0 (m, 2H); 5.9(s, 2H); 3.1 (br. 2H); 3.0 (br, 3H); 2.8 (br, 3H);2.9 (m, 1H); 1.5 (m, 1H); 1.39 (m, 1H). 12; 10ABD JO

4.55 452 12; 10ABD JP

3.18 452 12; 10ABD JQ

4.05 501 12; 10ABD JR

3.68 508 1HNMR(400 MHz, CD3OD): d 8.44-8.42 (m, 1H), 8.24-8.14 (m, 3H),7.99-7.95 (m, 1H), 7.27-7.21 (m, 1H), 7.07-6.98 (m, 2H), 5.91 (s, 2H),4.43-4.37 (m, 1H), 3.67-3.63 (m, 2H), 3.49-3.40 (m, 2H), 3.33-3.27 (m,), 3.16-3.03 (m, 2H), 1.94-1.86 (m, 2H), 1.54-1.46 (m, 6H). JS

3.48 507 12; 10ABD JT

3.61 535 12; 10ABD JU

3.61 603 12; 10ABD JV

584 12; 10ABD JW

3.58 439 1HNMR(400 MHz, CD3OD): d 7.99-7.97 (m, 1H), 7.90-7.88 (m, 1H),7.80 7.77 (m, 1H), 7.56-7.52 (m, 1H), 7.28 (s, 1H), 7.20-7.16 (m, 1H),7.10-7.03 (m, 2H), 5.58 (s, 2H), 3.27-3.13 (m, 5H), 2.18-2.13 (m, 1H),1.56-1.54 (m, 1H), 1.45-1.43 (m, 1H). 14; 31 JX

2.25 434 2AB; 6 JY

2.6 474 2AB; 6 JZ

2.3 446 2AB; 6 KA

2.5 468 2AB; 6 KB

2.3 475 2AB; 6 KC

1.95 406 2AB; 6 KD

2.55 496 2AB; 6 KE

2.45 482 2AB; 6 KF

2.6 496 2AB; 6 KG

2.5 500 2AB; 6 KH

1.85 483 2AB; 6 KI

1.85 483 2AB; 6 KJ

2.15 420 2AB; 6 KK

2.6 496 2AB; 6 KL

1.8 475 2AB; 6 KM

4.01 435 1; 7AB C; 8AB KN

2.4 421 1; 7AB C; 8AB KO

2.55 435 1; 7AB C; 8AB KP

2.7 449 1; 7AB C; 8AB KQ

3.06 393 1; 7AB C; 8A KR

4.16 341 1H NMR (CD3CN): d 7.65-7.4 (m, 5H); 7.35 (m, 1H); 6.95 (m, 3H);6.15 (br s, 1H); 5.95 (br s, 1H); 5.2 (s, 2H); 3.4-3.4 (m, 2H); 2.35 (m,1H); 1.6 (m, 1H); 1.47 (m, 1H). 35A; 7 ABC; 8 AC KS

3.91 453 1H NMR (CD3OD): d 8.19 (m, 1H), 8.05 (m, 1H), 7.87 (m, 1H),7.75 (s, 1H); 7.70 (m, 1H); 7.15 (m, 1H); 7.06 (m, 1H); 7.00 (m, 1H);5.70 (s, 2H), 4.06 (m, 2H); (s, 3H), 3.02-3.21 (m, 2H), 2.79 (s, 3H),2.26 (m, 1H), 1.53 (m, 2H), 1.14 (m, 3H) KT

3.51 327 1H NMR (CD3CN): d 7.65-7.45 (m, 5H); 7.4 (m, 2H); 7.1 (m, 2H);6.0 (br s, 1H); 5.65 (br s, 1H); 2.6 (m, 1H); 1.85 (m, 1H); 1.7 (m, 1H)4A; 2ABC; 3 KU

4.26 356 1H NMR (CD3CN): d 7.62-7.4 (m, 5H); 7.3 (m, 2H); 7.0 (m, 2H);5.2 (s, 2H); 4.2 (m, 2H); 2.6 (m, 1H); 2.05 (m, 1H); 2.85 (m, 1H), 1.25(m, 3H). 4 KV

4.06 341 1H NMR (CD3CN: D2O (1:1)): d 7.40 7.29 (m, 5H), 7.12 (m, 2H),6.88 (m, 2H), 5.03 (s, 2H), 3.08-2.85 (m, 2H), 2.06-2.02 (m, 1H),1.50-1.46 (m, 1H), 1.38-1.35 (m, 1H) 7ABC; 8AC KW

3.21 303 1H NMR (CD3OD): d 7.18 (m, 2H), 6.86 (m, 2H), 4.61 (s, 2H),3.23-3.09 (m, 2H), 2.16-2.13 (m, 1H), 1.81 (m, 3H), 1.55-1.51 (m, 1H),1.47-1.44 (m, 1H) 7ABC; 8AC KX

4.65 468 1H NMR(400 MHz, CD3OD): d 8.43-8.33 (m, 3H), 8.12-8.09 (m, 3H),7.94 7.90 (m, 1H), 7.73-7.68 (m, 3H), 7.28 7.26 (m, 2H), 7.11-7.09 (m,2H), 5.85(s, 2H), 3.27-3.12 (m, 2H), 2.16-2.12 (m, 1H), 1.56-1.53 (m,1H), 1.47 1.44 (m, 1H) 7ABC; 8AC KY

3.85 538 1H NMR(400 MHz, CD3OD): d 8.40-8.30 (m, 3H), 8.12-8.04 (m, 3H),7.90 7.87 (m, 1H), 7.69-7.67 (m, 3H), 7.18 7.06 (m, 4H), 5.84 (s, 2H),4.35-4.28 (m, 1H), 3.63-3.37 (m, 3H), 3.22-2.96 (m, 3H), 1.90-1.66 (m,3H), 1.54 1.51 (m, 1H), 1.46-1.42 (m, 1H). 9; 10A BD KZ

3.78 537 1HNMR(400 MHz, CD3OD): d 8.46-8.49 (m, 3H), 8.18-8.09 (m, 3H),8.00 7.96 (m, 1H), 7.79-7.70 (m, 3H), 7.17 7.09 (m, 4H), 5.87 (s, 2H),3.85-3.39 (m, 5H), 3.12-3.03 (m, 2H), 2.28-2.16 (m, 1H), 2.00-1.95 (m,2H), 1.54 1.35 (m, 2H). 9; 10A BD LA

3.81 538 1H NMR(400 MHz, CD3OD): d 8.39-8.29 (m, 3H), 8.12-8.03 (m, 3H),7.90 7.84 (m, 1H), 7.69-7.67 (m, 3H), 7.17 7.06 (m, 4H), 5.83 (s, 2H),4.30-4.27 (m, 1H), 3.62-3.39 (m, 3H), 3.26-3.08 (m, 3H), 2.01-1.63 (m,3H), 1.55 1.45 (m, 1H), 1.37-1.29 (m, 1H). 9; 10A BD LB

4.91 496 1H NMR(400 MHz, CD3OD): d 8.46-8.35 (m, 3H), 8.16-8.10 (m,3H)7.97-7.94 (m, 1H), 7.77-7.71 (m, 3H), 7.14 7.08 (m, 4H), 5.89 (s,2H), 3.07 (s, 2H), 2.96 (s, 3H), 2.78 (s, 3H), 1.93-1.86 (m, 1H),1.53-1.50 (m, 1H), 1.36 1.33 (m, 1H) 9; 10A BD LC

3.84 420 9; 10A BD LD

4.66 327 6A; 8A LE

326 5AB; 8A; 3B; 2B LF

4.76 355 6A; 9C LG

497 43 LH

456 15 LI

502 30B LJ

569 12ABC; 13, 33, 3 LK

597 12ABC; 13, 33, 3 LL

371 15 LM

493 14, .31

[0446] It will be appreciated by those skilled in the art that changescould be made to the embodiments described above without departing fromthe broad inventive concept thereof. It is understood, therefore, thatthis invention is not limited to the particular embodiments disclosed,but it is intended to cover modifications that are within the spirit andscope of the invention, as defined by the appended claims.

Therefore, we claim:
 1. A compound represented by Formula (I):

or a pharmaceutically acceptable salt, solvate or isomer thereof,wherein: M is —(C(R³⁰)(R⁴⁰))_(m)—, wherein m is 1 to 6; T is selectedfrom the group consisting of R²¹-substituted alkyl, cycloalkyl,heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl,—OR³, —C(O)R⁴, —C(O)OR³, —C(O)NR²⁴R²⁵, —C(O)NR²⁴OR³, —C(O)SR³, —NR²⁴R²⁵,—NR²⁵C(O)R⁴, —NR²⁵C(O)OR³, —NR²⁵C(O)NR²⁴R²⁵, —NR²⁵C(O)NR²⁴OR³, —SR³,—S(O)_(x)NR²⁴R²⁵, —S(O)_(x)NR²⁵OR³, —CN, —P(O)(R²⁴)(OR²⁴),—P(O)(OR²⁴)(OR²⁴), —C(R⁴)(═N(OR³)), —C(O)—AA—NR²⁴R²⁵ and—C(O)—AA—NR²⁵OR³, wherein each of the cycloalkyl, heterocycloalkyl,cycloalkenyl, heterocycloalkenyl, aryl and heteroaryl groups of T isindependently unsubstituted or substituted with one to fiveindependently selected R²⁰ moieties which can be the same or different,each R²⁰ moiety being independently selected from the group of R²⁰moieties below; V is selected from the group consisting of alkyl,R²¹-substituted alkyl, cycloalkyl, heterocycloalkyl, cycloalkenyl,heterocycloalkenyl, aryl, heteroaryl, —OR³, —C(O)R⁴,—(CR²³R²⁴)_(n1)C(O)OR³, —C(O)NR²⁴R²⁵. —(CR²³R²⁴)_(n1)C(O)NR²⁵OR³,—C(O)SR³, —NR²⁴R²⁵, —NR²⁵C(O)R⁴, —NR²⁵C(O)OR³, —NR²⁵C(O)NR²⁴R²⁵,—NR²⁵C(O)NR²⁴OR³, —SR³, —S(O)_(x)NR²⁴R²⁵, —S(O)_(x)NR²⁵OR³, —CN,—P(O)(R²⁴)(OR²⁴), —P(O)(OR²⁴)(OR²⁴), —C(R⁴)(═N(OR³)) —C(O)—AA—NR²⁴R²⁵and —C(O)—AA—NR²⁵OR³, wherein each of the cycloalkyl, heterocycloalkyl,cycloalkenyl, heterocycloalkenyl, aryl and heteroaryl groups of V isindependently unsubstituted or substituted with one to threeindependently selected R²⁰ moieties which can be the same or different,each R²⁰ moiety being independently selected from the group ofR²⁰moieties below; W is selected from the group consisting of

 a covalent bond, —(C(R³)(R⁴))_(n2)—, —O—, —S—, and —N(Z)—; X isselected from the group consisting of alkylene, cycloalkylene,heterocycloalkylene, arylene, heteroarylene and —C≡C—, wherein each ofthe alkylene, cycloalkylene, heterocycloalkylene, arylene orheteroarylene groups of X is independently unsubstituted or substitutedwith one to four independently selected R²⁰ moieties which can be thesame or different, each R²⁰ moiety being independently selected from thegroup of R²⁰moieties below; U is selected from the group consisting of acovalent bond, —(C(R³)(R⁴))_(p)—, —Y—(C(R³)(R⁴))_(q)—,—(C(R³)(R⁴))_(t)—Y—, and —Y—; Y is selected from the group consisting of—O—, —S(O)_(x)—, —N(Z)—, —C(O)—, —OC(O)—, —C(O)N(R²⁴)—,—N(R²⁴)C(O)N(R²⁵)—; —N(R²⁴)S(O)—, N(R²⁴)S(O)₂—, —S(O)N(R²⁴)—, and—S(O)₂N(R²⁴)—; Z is selected from the group consisting of —R³, —C(O)R³,—S(O)_(x)R³ and —C(O)NR³R⁴; n is 0 to 2; n1 is 0 to 2; n2 is 1 to 2; pis 1 to 4; q is 1 to 4; t is 1 to 4; v is 1 to 3; x is 0 to 2; y is 0 to3; AA is

 wherein R³¹ and R³² are the same or different and are eachindependently selected from the group consisting of H, alkyl,cycloalkyl, aryl, heteroaryl, —NR²⁴R²⁵, —(CH₂)₃NH(C═NH)NH₂, —CH₂C(O)NH₂,—CH₂C(O)OH, —CH₂SH, —CH₂S—SCH₂CH(NH₂)C(O)OH, —CH₂CH₂C(O)OH,—CH₂CH₂C(O)NH₂, —(CH₂)₄NH₂, —CH₂CH₂CH(OH)CH₂NH₂, —CH₂CH(CH₃)₂,—CH(CH₃)CH₂(CH₃), —CH₂CH₂SCH₃, —CH₂OH, —CH(OH)(CH₃),

or R³¹ and R³², together with the N to which R³¹ is attached and the Cto which R³¹ is attached, form a 5-membered ring which is unsubstitutedor independently substituted with a hydroxyl group; R¹ is selected fromthe group consisting of alkyl, R²¹-substituted alkyl, cycloalkyl,heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl,—C≡CR³ and —CR³═CR⁴R⁵, wherein each of the alkyl, cycloalkyl,heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl and heteroarylgroups of R¹ is independently unsubstituted or substituted with one tofive independently selected R²⁰ moieties which can be the same ordifferent, each R²⁰ moiety being independently selected from the groupof R²⁰ moieties below, each R², R⁴ and R⁵ is the same or different andeach is independently selected from the group consisting of H, halo,alkyl, R²²-substituted alkyl, cycloalkyl, heterocycloalkyl,cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, —OR⁶, —C(O)R⁷,—C(O)OR⁶, —NR²⁴R²⁵, —NR²⁴C(O)R²⁵, —N(═C—O—NR²⁴R²⁵), —NR²⁴S(O)₂R²⁵,wherein each of the cycloalkyl, heterocycloalkyl, cycloalkenyl,heterocycloalkenyl, aryl and heteroaryl groups of R², R⁴ and R⁵ isindependently unsubstituted or substituted with one to fourindependently selected alkyl, R²²-substituted alkyl or R²² moietieswhich can be the same or different, each R²² moiety being independentlyselected from the group of R²² moieties below; each R³ is the same ordifferent and is independently selected from the group consisting of H,alkyl, R²²-substituted alkyl, cycloalkyl, heterocycloalkyl,cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, —OR⁶, —C(O)R⁷,—C(O)OR⁶, —NR²⁴R²⁵, —NR²⁴C(O)R²⁵, —N(═C—O—NR²⁴R²⁵) and —NR²⁴S(O)₂R²⁵,each of the cycloalkyl, heterocycloalkyl, cycloalkenyl,heterocycloalkenyl, aryl and heteroaryl groups of R³ is independentlyunsubstituted or substituted with one to four independently selectedalkyl, R²²-substituted alkyl or R²² moieties which can be the same ordifferent, each R²² moiety being independently selected from the groupof R²² moieties below; each R⁶ is independently selected from the groupconsisting of H, alkyl and —OCF₃; each R⁷ is independently selected fromthe group consisting of H, alkyl, heteroaryl and —CF₃; each R²⁰ isindependently selected from the group consisting of: alkyl,R²¹-substituted alkyl, —OR³, halo, —CN, —NO₂, —NR²⁴R²⁵, —C(O)R³,—C(O)OR³, —C(O)NR²⁴R²⁵, —S(O)_(x)NR²⁴R²⁵, —S(O)_(x)R⁵, —CF₃, —OCF₃,—CF₂CF₃, —C(═NOH)R³, aryl, halo-substituted aryl, heteroaryl,cycloalkyl, heterocycloalkyl, —N(R²⁵)S(O)_(x)R⁵, —N(R²⁵)C(O)R⁵, and—N(R²⁵)C(O)NR²⁴R²⁵, wherein each of the aryl, halo-substituted aryl,heteroaryl, cycloalkyl and heterocycloalkyl groups of R²⁰ isindependently unsubstituted or substituted with one to fourindependently selected R²² moieties which can be the same or different,each R²² moiety being independently selected from the group of R²³moieties below, or two R²⁰ groups taken together with the carbon towhich both R²⁰ groups are attached is

R²¹ is one to three substituents independently selected from the groupconsisting of: —OR³, halo, —CN, —NO₂, —NR²⁴R²⁵, —C(O)R³, —C(O)OR³,—C(O)NR²⁴R²⁵, —S(O)_(x)NR²⁴R²⁵, —SO_(x)R⁵, —CF₃, —OCF₃, —CF₂CF₃,—C(═NOH)R³, R²³-substituted alkyl, aryl, heteroaryl, cycloalkyl,heterocycloalkyl, —N(R²⁵)S(O)_(x)R⁵, —N(R²⁵)C(O)R⁵, and—N(R²⁵)C(O)NR²⁴R²⁵; wherein each of the aryl, halo-substituted aryl,heteroaryl, cycloalkyl, and heterocycloalkyl groups of R²¹ isindependently unsubstituted or substituted with one to fourindependently selected R²³ moieties which can be the same or different,each R²³ moiety being independently selected from the group of R²³moieties below, or two R²¹ groups taken together with the carbon towhich both R²¹ groups are attached is

each R²² is independently selected from the group consisting of: halo,alkynyl, aryl, heteroaryl, —OR²⁴, —(C₁-C₆ alkyl)-OR²⁴, —CN, —NO₂,—NR²⁴R²⁵, —C(O)R²³, —C(O)OR²³, —C(O)NR²⁴R²⁵, —S(O)_(x)NR²⁴R²⁵,—S(O)_(x)R²³, —CF₃, —OCF₃, —CF₂CF₃, —C(═NOH)R²³, —N(R²⁴)S(O)_(x)R²⁵,—N(R²⁴)C(O)R²⁵, and —N(R²⁴)C(O)NR²⁴R²⁵, or two R²² groups taken togetherwith the carbon to which both R²² groups are attached is

each R²³ is independently selected from the group consisting of H,hydroxyl, halo and alkyl; each R²⁴ is independently selected from thegroup consisting of H and alkyl; each R²⁵ is independently selected fromthe group consisting of H, hydroxyl, alkyl, hydroxyalkyl, aryl,cycloalkyl, heteroaryl, —NR²⁴R²⁴, —(C₁ to C₆ alkyl)NR²⁴N²⁴, —CF₃ and—S(O)_(x)R²³; each R²⁶ is independently selected from the groupconsisting of H, hydroxyl, alkyl, hydroxyalkyl, aryl, cycloalkyl,heteroaryl and —NR³R⁴; R²⁷ is independently selected from the groupconsisting of heteroaryl, heterocycloalkyl and —NR²⁴R²⁵; R³⁰ isindependently selected from the group consisting of H and R²⁰substituent groups above; R⁴⁰ is independently selected from the groupconsisting of H and R²⁰ substituent groups above, or R³⁰ and R⁴⁰, takentogether with the carbon to which R³⁰ and R⁴⁰ are attached, is

 with the proviso that at least one of V or T is selected from the groupconsisting of —C(O)N(R³)(OR⁴), —C(O)OR³ and —C(O)NR²⁴R²⁵, and when—(W)_(n)—X—U— is alkylene, R¹ is not alkyl.
 2. The compound according toclaim 1, wherein m is
 4. 3. The compound according to claim 1, wherein mis
 3. 4. The compound according to claim 1, wherein m is
 2. 5. Thecompound according to claim 1, wherein m is
 1. 6. The compound accordingto claim 1, wherein R³⁰ is H or —(C₁-C₆)alkyl.
 7. The compound accordingto claim 1, wherein R⁴⁰ is H or —(C₁-C₆)alkyl.
 8. The compound accordingto claim 1, wherein T is selected from the group consisting of —C(O)R⁴,—C(O)OR³, —C(O)NR²³R²⁵, and —C(O)NR²³OR³.
 9. The compound according toclaim 8, wherein T is —C(O)R⁴ in which R⁴ is a pyrrolidinyl ring that isunsubstituted or substituted with one to three R²² moieties which areeach independently selected from the group consisting of —OR²⁴, —(C₁-C₆alkyl)-OR²⁴ and —NR²³R²⁴.
 10. The compound according to claim 8, whereinT is —C(O)OR³ in which R³ is alkyl.
 11. The compound according to claim8, wherein T is —C(O)NR²³R²⁵ in which R²³ is H or alkyl and R²⁵ is H,alkyl or —(C₁ to C₆ alkyl)NR²³N²⁴.
 12. The compound according to claim8, wherein T is —C(O)NR²³OR³ in which R²³ is H or alkyl and R³ is H oralkyl.
 13. The compound according to claim 1, wherein V is —C(O)NR²³OR³in which R²³ is H or alkyl and R³ is H or alkyl.
 14. The compoundaccording to claim 1, wherein V is —C(O)OR³ in which R³ is alkyl. 15.The compound according to claim 1, wherein W is —C(R³)(R⁴)— in which R³is H and R⁴ is H.
 16. The compound according to claim 1, wherein W is acovalent bond.
 17. The compound according to claim 1, wherein n is 1.18. The compound according to claim 1, wherein X is arylene which isunsubstituted or substituted with one to two independently selected R²⁰moieties which can be the same or different.
 19. The compound accordingto claim 18, wherein X is phenylene which is unsubstituted orsubstituted with one or two halo substituents which can be the same ordifferent.
 20. The compound according to claim 1, wherein X is aheteroarylene which is unsubstituted or substituted with one to twoindependently selected R²⁰ moieties which can be the same or different.21. The compound according to claim 20, wherein X is a heteroaryleneselected from the group consisting of

which is unsubstituted or substituted with one or two halo substituentswhich can be the same or different.
 22. The compound according to claim1, wherein U is —Y—(C(R³)(R⁴))_(q)—.
 23. The compound according to claim22, wherein Y is —O—.
 24. The compound according to claim 22, wherein qis 1, R³ is H or alkyl and R⁴ is H or alkyl.
 25. The compound accordingto claim 1, wherein R¹ is selected from the group consisting ofcycloalkyl, aryl and heteroaryl, wherein each of the cycloalkyl, aryland heteroaryl groups of R¹ is independently unsubstituted orsubstituted with one to five independently selected R²⁰ moieties whichcan be the same or different, each R²⁰ moiety being independentlyselected from the group of R²⁰ moieties,
 26. The compound according toclaim 25, wherein R¹ is a cycloalkyl group selected from the groupconsisting of cyclopropyl, cyclobutyl and cyclohexyl, wherein each ofthe cycloalkyl groups is independently unsubstituted or substituted withone to five independently selected R²⁰ moieties which can be the same ordifferent, each R²⁰ moiety being independently selected from the groupof R²⁰ moieties.
 27. The compound according to claim 25, wherein R¹is anaryl group selected from the group consisting of phenyl, naphthyl,indanyl and tetrahydronaphthalenyl, wherein each of the aryl groups isindependently unsubstituted or substituted with one to fiveindependently selected R²⁰ moieties which can be the same or different,each R²⁰ moiety being independently selected from the group of R²⁰moieties.
 28. The compound according to claim 25, wherein R¹ is aheteroaryl group selected from the group consisting of chromanyl,quinolyl, isoquinolyl, triazolyl, pyridyl, imidazolyl, thiazolyl,benzodioxolyl and

wherein each of the heteroaryl groups is independently unsubstituted orsubstituted with one to five independently selected R²⁰ moieties whichcan be the same or different, each R²⁰ moiety being independentlyselected from the group of R²⁰ moieties.
 29. The compound according toclaim 25, wherein R¹ is (1) a fused bicyclic aryl group which isunsubstituted or substituted with one to three independently selectedR²⁰ moieties which can be the same or different or (2) a fused bicyclicheteroaryl group which is unsubstituted or substituted with one to threeindependently selected R²⁰ moieties which can be the same or different.30. The compound according to claim 1, wherein R² is H.
 31. The compoundaccording to claim 1, wherein each R³ is independently H, alkyl or aryl.32. The compound according to claim 1, wherein each R⁴ is independentlyH, alkyl or aryl.
 33. The compound according to claim 1, wherein each R⁵is independently H, alkyl or aryl.
 34. The compound according to claim1, wherein each R²⁰ is independently selected from the group consistingof alkyl, R²¹-substituted alkyl, —OR³, halo, —CN, —NO₂, —NR³R⁴,—C(O)OR³, —S(O)_(x)R⁵, —CF₃, —OCF₃, aryl, heteroaryl, cycloalkyl,wherein each of the aryl, heteroaryl and cycloalkyl groups of R²⁰ isindependently unsubstituted or substituted with one to fourindependently selected R²² moieties which can be the same or different,each R²² moiety being independently selected from the group of R²³moieties.
 35. The compound according to claim 34, wherein R²⁰ is aheteroaryl group selected from the group consisting of pyrazinyl,pyrrolyl, pyridyl and morpholinyl.
 36. The compound according to claim34, wherein R²⁰ is a cycloalkyl selected from the group consisting ofcyclopropyl, cyclobutyl and cyclohexyl.
 37. The compound according toclaim 34, wherein each R²⁰ moiety is selected from the group consistingof —(C₁-C₆)alkyl and aryl.
 38. The compound according to claim 1,wherein M is —(C(R³⁰)(R⁴⁰)_(m)—, wherein m is 1 to 4; V is —C(O)OR³ or—C(O)NR²⁵OR³; T is R²¹-substituted alkyl, —CN, —C(O)OR³, —C(O)NR²⁵OR³,—C(O)NR²⁴R²⁵, —C(O)R⁴ or —C(R⁴)(═N(OR³)); W is a covalent bond or—(C(R³)(R⁴))_(n2); X is arylene or heteroarylene, each of which can beindependently unsubstituted or substituted with one to fiveindependently selected R²⁰ moieties; R¹ is cycloalkyl, aryl, heteroaryl,each of which can be independently unsubstituted or substituted with oneto four independently selected R²⁰ moieties; and R² is H.
 39. Thecompound according to claim 38, wherein m is
 1. 40. The compoundaccording to claim 39, wherein m is
 2. 41. The compound according toclaim 38, wherein R³⁰ is H or —(C₁-C₆)alkyl and R⁴⁰ is H or—(C₁-C₆)alkyl.
 42. The compound according to claim 38, wherein T isselected from the group consisting of —C(O)R⁴, —C(O)OR³, —C(O)NR²³R²⁵,and —C(O)NR²³OR³.
 43. The compound according to claim42, wherein T is—C(O)OR³ or —C(O)NR²³R²⁵.
 44. The compound according to claim 38,wherein V is —C(O)NR²³OR³ in which R²³ is H or alkyl and R³ is H oralkyl.
 45. The compound according to claim 38, wherein W is —C(R³)(R⁴)—in which n2 is 1, R³ is H and R⁴ is H or W is a covalent bond.
 46. Thecompound according to claim 38, wherein X is arylene which isunsubstituted or substituted with one to two independently selected R²⁰moieties which can be the same or different.
 47. The compound accordingto claim 38, wherein U is —Y—(C(R³)(R⁴))_(q)—.
 48. The compoundaccording to claim 47, wherein Y is —O—, q is 1, R³ is H or alkyl and R⁴is H or alkyl.
 49. The compound according to claim 38, wherein R¹ isselected from the group consisting of aryl and heteroaryl, wherein eachof the aryl and heteroaryl groups of R¹ is independently unsubstitutedor substituted with one to five independently selected R²⁰ moietieswhich can be the same or different, each R²⁰ moiety being independentlyselected from the group of R²⁰ moieties,
 50. The compound according toclaim 49, wherein R¹ is an aryl group selected from the group consistingof phenyl, naphthyl, indanyl and tetrahydronaphthalenyl, wherein each ofthe aryl groups is independently unsubstituted or substituted with oneto five independently selected R²⁰ moieties which can be the same ordifferent, each R²⁰ moiety being independently selected from the groupof R²⁰ moieties.
 51. The compound according to claim 49, wherein R¹ is aheteroaryl group selected from the group consisting of chromanyl,quinolyl, isoquinolyl,

triazolyl, pyridyl, imidazolyl, thiazolyl, benzodioxolyl and, whereineach of the heteroaryl groups is independently unsubstituted orsubstituted with one to five independently selected R²⁰ moieties whichcan be the same or different, each R²⁰ moiety being independentlyselected from the group of R²⁰ moieties.
 52. The compound according toclaim 38, wherein each R³ is independently H, alkyl or aryl, wherein thealkyl or aryl groups can be unsubstituted or substituted with one tofour independently selected R²² moieties.
 53. The compound according toclaim 38, wherein each R⁴ is independently H, alkyl or aryl.
 54. Thecompound according to claim 38, wherein each R⁵ is independently H,alkyl or aryl.
 55. The compound according to claim 38, wherein each R²⁰is independently selected from the group consisting of alkyl,R²¹-substituted alkyl, —OR³, halo, —CN, —NO₂, —NR³R⁴, —C(O)OR³,—S(O)_(x)R⁵, —CF₃, —OCF₃, aryl, heteroaryl, cycloalkyl, wherein each ofthe aryl, heteroaryl and cycloalkyl groups of R²⁰ is independentlyunsubstituted or substituted with one to four independently selected R²²moieties which can be the same or different, each R²² moiety beingindependently selected fromthe group of R²³ moieties.
 56. A compoundselected from the group consisting of:

or a pharmaceutically acceptable salt, solvate or isomer thereof.
 57. Acompound according to claim 56, which is selected from the groupconsisting of

or a pharmaceutically acceptable salt, solvate or isomer thereof.
 58. Acompound represented by Formula (I):

or a pharmaceutically acceptable salt, solvate or isomer thereof,wherein: M is —(C(R³⁰)(R⁴⁰))_(m)—, wherein m is 1 to 6; T is selectedfrom the group consisting of R²¹-substituted alkyl, cycloalkyl,heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl,—OR³, —C(O)R⁴, —C(O)OR³, —C(O)NR²⁴R²⁵, —C(O)NR²⁴OR³, —C(O)SR³, —NR²⁴R²⁵,—NR²⁵C(O)R⁴, —NR²⁵C(O)OR³, —NR²⁵C(O)NR²⁴R²⁵, —N R²⁵C(O)NR²⁴OR³,—NR²⁵S(O)_(x)R³, —SR³, —S(O)_(x)NR²⁴R²⁵, —S(O)_(x)NR²⁵OR³, —CN,—P(O)(R²⁴)(OR²⁴), —P(O)(OR²⁴)(OR²⁴), —C(R⁴)(═N(OR³)), —C(O)—AA—NR²⁴R²⁵and —C(O)—AA—NR²⁵OR³, wherein each of the cycloalkyl, heterocycloalkyl,cycloalkenyl, heterocycloalkenyl, aryl and heteroaryl groups of T isindependently unsubstituted or substituted with one to fiveindependently selected R²⁰ moieties which can be the same or different,each R²⁰ moiety being independently selected from the group of R²⁰moieties below; V is selected from the group consisting of alkyl,R²¹-substituted alkyl, cycloalkyl, heterocycloalkyl, cycloalkenyl,heterocycloalkenyl, aryl, heteroaryl, —OR³, —C(O)R⁴,—(CR²³R²⁴)_(n1)C(O)OR³, —C(O)NR²⁴R²⁵, —(CR²³R²⁴)_(n1)C(O)NR²⁵OR³,—C(O)SR³, —NR²⁴R²⁵, —NR²⁵C(O)R⁴, —NR²⁵C()OR³, —NR²⁵C(O)NR²⁴R²⁵,—NR²⁵C(O)NR²⁴OR³, —NR²⁵S(O)_(x)R³, —SR³, —S(O)_(x)NR²⁴R²⁵,—S(O)_(x)NR²⁵OR³, —CN, —P(O)(R²⁴)(OR²⁴), —P(O)(OR²⁴)(OR²⁴),—C(R⁴)(═N(OR³)), —C(O)—AA—NR²⁴R²⁵ and —C(O)—AA—NR²⁵OR³, wherein each ofthe cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryland heteroaryl groups of V is independently unsubstituted or substitutedwith one to three independently selected R²⁰ moieties which can be thesame or different, each R²⁰ moiety being independently selected from thegroup of R²⁰moieties below; W is selected from the group consisting of

 a covalent bond, —(C(R³)(R⁴))_(n2)—, —O—, —S—, and —N(Z)—; X isselected from the group consisting of alkylene, cycloalkylene,heterocycloalkylene, arylene, heteroarylene and —C≡C—, wherein each ofthe alkylene, cycloalkylene, heterocycloalkylene, arylene orheteroarylene groups of X is independently unsubstituted or substitutedwith one to four independently selected R²⁰ moieties which can be thesame or different, each R²⁰ moiety being independently selected from thegroup of R²⁰moieties below; U is selected from the group consisting of acovalent bond, —(C(R³)(R⁴))_(p)—, —Y—(C(R³)(R⁴))_(q)—,—(C(R³)(R⁴))_(t)—Y—, and —Y—; Y is selected from the group consisting of—O—, —S(O)_(x)—, —N(Z)—, —C(O)—, —OC(O)—, —C(O)N(R²⁴)—, —N(R²⁴)C(O)—,—N(R²⁴)C(O)N(R²⁵)—, —N(R²⁴)S(O)—, —N(R²⁴)S(O)₂—, —S(O)N(R²⁴)—, and—S(O)₂N(R²⁴)—; Z is selected from the group consisting of —R³, —C(O)R³,—S(O)_(x)R³ and —C(O)NR³R⁴; n is 0 to 2; n1 is 0 to 2; n2 is 1 to 2; pis 1 to 4; q is 1 to 4; t is 1 to 4; v is 1 to 3; x is 0 to 2; y is 0 to3; AA is

 wherein R³¹ and R³² are the same or different and are eachindependently selected from the group consisting of H, alkyl,cycloalkyl, aryl, heteroaryl, —NR²⁴R²⁵, —(CH₂)₃NH(C═NH)NH₂, —CH₂C(O)NH₂,—CH₂C(O)OH, —CH₂SH, —CH₂S—SCH₂CH(NH₂)C(O)OH, —CH₂CH₂C(O)OH,—CH₂CH₂C(O)NH₂, —(CH₂)₄NH₂, —CH₂CH₂CH(OH)CH₂NH₂, —CH₂CH(CH₃)₂,—CH(CH₃)CH₂(CH₃), —CH₂CH₂SCH₃, —CH₂OH, —CH(OH)(CH₃),

or R³¹ and R³², together with the N to which R³¹ is attached and the Cto which R³¹ is attached, form a 5-membered ring which is unsubstitutedor independently substituted with a hydroxyl group; R¹ is selected fromthe group consisting of alkyl, R²¹-substituted alkyl, cycloalkyl,heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl,—C≡CR³ and —CR³═CR⁴R⁵, wherein each of the alkyl, cycloalkyl,heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl and heteroarylgroups of R¹ is independently unsubstituted or substituted with one tofive independently selected R²⁰ moieties which can be the same ordifferent, each R²⁰ moiety being independently selected from the groupof R²⁰ moieties below, each R², R⁴ and R⁵ is the same or different andeach is independently selected from the group consisting of H, halo,alkyl, R²²-substituted alkyl, cycloalkyl, heterocycloalkyl,cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, —OR⁶, —C(O)R⁷,—C(O)OR⁶, —NR²⁴R²⁵, —NR²⁴C(O)R²⁵, —N(═C—O—NR²⁴ R²⁵), —NR²⁴S(O)₂R²⁵,wherein each of the cycloalkyl, heterocycloalkyl, cycloalkenyl,heterocycloalkenyl, aryl and heteroaryl groups of R², R⁴ and R⁵ isindependently unsubstituted or substituted with one to fourindependently selected alkyl, R²²-substituted alkyl or R²² moietieswhich can be the same or different, each R²² moiety being independentlyselected from the group of R²² moieties below; each R³ is the same ordifferent and is independently selected from the group consisting of H,alkyl, R²²-substituted alkyl, cycloalkyl, heterocycloalkyl,cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, —OR⁶, —C(O)R⁷,—C(O)OR⁶, —NR²⁴R²⁵, —NR²⁴C(O)R²⁵, —N(═C—O—NR²⁴R²⁵) and —NR²⁴S(O)₂R²⁵,each of the cycloalkyl, heterocycloalkyl, cycloalkenyl,heterocycloalkenyl, aryl and heteroaryl groups of R³ is independentlyunsubstituted or substituted with one to four independently selectedalkyl, R²²-substituted alkyl or R²² moieties which can be the same ordifferent, each R²² moiety being independently selected from the groupof R²² moieties below; each R⁶ is independently selected from the groupconsisting of H, alkyl and —OCF₃; each R⁷ is independently selected fromthe group consisting of H, alkyl, heteroaryl and —CF₃; each R²⁰ isindependently selected from the group consisting of: alkyl,R²¹-substituted alkyl, —OR³, halo, —CN, —NO₂, —NR²⁴R²⁵, —C(O)R³,—C(O)OR³, —C(O)NR²⁴R²⁵, —S(O))_(x)NR²⁴R²⁵, —S(O)_(x)R⁵, —CF₃, —OCF₃,—CF₂CF₃, —C(═NOH)R³, aryl, halo-substituted aryl, heteroaryl,cycloalkyl, heterocycloalkyl, —N(R²⁵)S(O)_(x)R⁵, —N(R²⁵)C(O)R⁵, and—N(R²⁵)C(O)NR²⁴R²⁵, wherein each of the aryl, halo-substituted aryl,heteroaryl, cycloalkyl and heterocycloalkyl groups of R²⁰ isindependently unsubstituted or substituted with one to fourindependently selected R²² moieties which can be the same or different,each R²² moiety being independently selected from the group of R²³moieties below, or two R²⁰ groups taken together with the carbon towhich both R²⁰ groups are attached is

R²¹ is one to three substituents independently selected from the groupconsisting of: —OR³, halo, —CN, —NO₂, —NR²⁴R²⁵, —C(O)R³, —C(O)OR³—C(O)NR²⁴R²⁵, —S(O)_(x)NR²⁴R²⁵, —SO_(x)R⁵, —CF₃, —OCF₃, —CF₂CF₃,—C(═NOH)R³, R²³-substituted alkyl, aryl, heteroaryl, cycloalkyl,heterocycloalkyl, —N(R²⁵)S(O)_(x)R⁵, —N(R²⁵)C(O)R⁵, and—N(R²⁵)C(O)NR²⁴R²⁵; wherein each of the aryl, halo-substituted aryl,heteroaryl, cycloalkyl, and heterocycloalkyl groups of R²¹ isindependently unsubstituted or substituted with one to fourindependently selected R²³ moieties which can be the same or different,each R²³ moiety being independently selected from the group of R²³moieties below, or two R²¹ groups taken together with the carbon towhich both R²¹ groups are attached is

each R²² is independently selected from the group consisting of: halo,alkynyl, aryl, heteroaryl, —OR²⁴, —(C₁-C₆ alkyl)-OR²⁴, —CN, —NO₂,—NR²⁴R²⁵, —C(O)R²³, —C(O)R²³, —C(O)NR²⁴R²⁵, —S(O)_(x)NR²⁴R²⁵,—S(O)_(x)R²³, —CF₃, —OCF₃, —CF₂CF₃, —C(═NOH)R²³, —N(R²⁴)S(O)_(x)R²⁵,—N(R²⁴)C(O)R²⁵, and —N(R²⁴)C(O)NR²⁴R²⁵, or two R²² groups taken togetherwith the carbon to which both R²² groups are attached is

each R²³ is independently selected from the group consisting of H,hydroxyl, halo and alkyl; each R²⁴ is independently selected from thegroup consisting of H and alkyl; each R²⁵ is independently selected fromthe group consisting of H, hydroxyl, alkyl, hydroxyalkyl, aryl,cycloalkyl, heteroaryl, —NR²⁴R²⁴, —(C₁ to C₆ alkyl)NR²⁴N²⁴, —CF₃ and—S(O)_(x)R²³; each R²⁶ is independently selected from the groupconsisting of H, hydroxyl, alkyl, hydroxyalkyl, aryl, cycloalkyl,heteroaryl and —NR³R⁴; R²⁷ is independently selected from the groupconsisting of heteroaryl, heterocycloalkyl and —NR²⁴R²⁵; R³⁰ isindependently selected from the group consisting of H and R²⁰substituent groups above; R⁴⁰ is independently selected from the groupconsisting of H and R²⁰ substituent groups above, or R³⁰ and R⁴⁰, takentogether with the carbon to which R³⁰ and R⁴⁰ are attached, is

 with the provisos that at least one of V or T is selected from thegroup consisting of —C(O)N(R³)(OR⁴), —C(O)OR³ and —C(O)NR²⁴R²⁵, and when—(W)_(n)—X—U— is alkylene, R¹ is not alkyl, and when —(W)_(n)—X— isalkylene, —Y— is not —N(R²⁴)C(O)—, and when one of T or V is—NR²⁵S(O)_(x)R³, the other of T or V is not —C(O)NR²⁵OR³.
 59. Apharmaceutical composition comprising a therapeutically effective amountof a compound of claim 1 or a pharmaceutically acceptable addition salt,solvate or isomer thereof, in combination with a pharmaceuticallyacceptable carrier.
 60. A pharmaceutical composition for the treatmentor prevention of inflammation in a subject, comprising an effectiveamount of a combination of a compound of claim 1 or a pharmaceuticallyacceptable salt, solvate or isomer thereof, an anti-inflammatory agentdifferent from the compound of claim 1 and a pharmaceutically acceptablecarrier.
 61. A method for treating or preventing an inflammatorydisorder comprising administering to a subject in need thereof atherapeutically effective amount of a compound of claim 1 or apharmaceutically acceptable salt, solvate or isomer thereof.
 62. Amethod of treating a condition or disease mediated by MMPs, TNF-α,aggrecanase, or a combination thereof in a subject comprising:administering to the subject in need of such treatment a therapeuticallyeffective amount of a compound of claim 1 or a pharmaceuticallyacceptable salt, solvate or isomer thereof.
 63. A method of treating acondition or disease selected from the group consisting of rheumatoidarthritis, osteoarthritis, periodontitis, gingivitis, cornealulceration, solid tumor growth and tumor invasion by secondarymetastases, neovascular glaucoma, inflammatory bowel disease, multiplesclerosis and psoriasis in a subject, comprising: administering to thesubject in need of such treatment a therapeutically effective amount ofa compound of claim 1 or a pharmaceutically acceptable salt, solvate orisomer thereof.
 64. A method of treating a condition or disease selectedfrom the group consisting of fever, cardiovascular conditions,hemorrhage, coagulation, cachexia, anorexia, alcoholism, acute phaseresponse, acute infection, shock, graft versus host reaction, autoimmunedisease and HIV infection in a subject comprising administering to thesubject in need of such treatment a therapeutically effective amount ofa compound of claim 1 or a pharmaceutically acceptable salt, solvate orisomer thereof.
 65. A method of treating a condition or disease selectedfrom the group consisting of septic shock, haemodynamic shock, sepsissyndrome, post ischaemic reperfusion injury, malaria, mycobacterialinfection, meningitis, psoriasis, congestive heart failure, fibroticdiseases, cachexia, graft rejection, cancers such as cutaneous T-celllymphoma, diseases involving angiogenesis, autoimmune diseases, skininflammatory diseases, inflammatory bowel diseases such as Crohn'sdisease and colitis, osteo and rheumatoid arthritis, ankylosingspondylitis, psoriatic arthritis, adult Still's disease, ureitis,Wegener's granulomatosis, Behcehe disease, Sjogren's syndrome,sarcoidosis, polymyositis, dermatomyositis, multiple sclerosis,radiation damage, hyperoxic alveolar injury, periodontal disease, HIV,non-insulin dependent diabetes mellitus, systemic lupus erythematosus,glaucoma, sarcoidosis, idiopathic pulmonary fibrosis, bronchopulmonarydysplasia, retinal disease, scleroderma, osteoporosis, renal ischemia,myocardial infarction, cerebral stroke, cerebral ischemia, nephritis,hepatitis, glomerulonephritis, cryptogenic fibrosing aveolitis,psoriasis, transplant rejection, atopic dermatitis, vasculitis, allergy,seasonal allergic rhinitis, reversible airway obstruction, adultrespiratory distress syndrome, asthma, chronic obstructive pulmonarydisease (COPD) and bronchitis in a subject comprising administering tothe subject in need of such treatment a therapeutically effective amountof a compound of claim 1 or a pharmaceutically acceptable salt, solvateor isomer thereof.